TW200536830A - 1-(2H)-isoquinolone derivative - Google Patents

Abstract

Disclosed is a compound represented by the formula (1) below, a prodrug thereof or their pharmacologically acceptable salt. Also disclosed is a medical drug or medical drug composition containing the compound. (1) [In the formula, Y1 and Y4 respectively represent a hydrogen atom or a halogen atom; one of Y2 and Y3 represents -NR1R2 and the other represents a hydrogen atom or a halogen atom; X represents an optionally substituted aryl group or heteroaryl group; R1 represents a hydrogen atom or an optionally substituted C1-8 alkyl group; R2 represents a C1-8 alkyl group substituted by one or more substituents, -COOR<3>, -COR4, -COSR5, -CONR6R7, -NR22R23 or -C=NR24R25; and R1 and R2 may combine with a nitrogen atom bonded thereto to form a 4-10 membered heterocyclic ring containing at least one nitrogen atom (and this heterocyclic ring may be substituted by one or more substituents selected from group C).]

Description

200536830 九 IX. Description of the invention [Technical field to which the invention belongs] The present invention is a novel 1 1 (2 Η) -isoquinolinone derivative and a medicine using these as an active ingredient, especially for diseases such as solid cancer Therapeutic drugs are useful anti-malignant agents. [Prior art]

There have been many reports on the synthesis method of a 1- (2Η) -isoquinolinone derivative having a substituent at the 3rd position. For example, a method for synthesizing 1- (2Η) -isoD-quinolinone derivatives by using ammonium in 3-arylisocoumarin derivatives proposed by Rose in 1988 (see Non-Patent Document 1) ). Also, in 1982, Poindexter proposed a method for synthesizing a 1- (2Η) -isoquinolinone derivative by the reaction of N, 2-dimethylbenzidine and a nitrile derivative (see Non-Patent Document 2). On the other hand, the pharmacological activity of such isoquinolinone derivatives has also been proposed. Researchers of the company Oct Amer have proposed an isoquinolinone derivative having an anti-inflammatory effect (see Patent Document 1). Researchers at Guilford Company have proposed that 3-phenyl-1,1- (2H) -iso1: quinolinone has a blocking activity against poly (ADP-ribose) polymerase and can be used as a radiation sensitizer (see Patent Document 3). In addition, for isoquinolinone derivatives with anticancer effects, researchers in Du Pont proposed in 1989 that 3- (1- (L) group) 1- (2H) -isoquinolinone derivatives have Report on anticancer effect (see Patent Document 2). Then, WonJea Chos reported on 3-arylisofluorinone derivatives with anticancer effects (see Non-Patent Document 3-6-200536830 (2) to 8). However, the anticancer effect of these isod | linenone derivatives is not necessarily sufficient ', so compounds having higher anticancer activity and better physical properties are expected.

[Patent Literature 1] International Publication No. 9 8/5 1 3 0 7 [Patent Literature 2] US Patent No. 4 9 4 2 1 6 3 Specification [Patent Literature 3] International Publication No. 99/1 1 624 [ Non-Patent Literature 1] J. Chem · Soc. (C), pp. 2205-2208 (1968) [Non-Patent Literature 2] J. Org. Chem ·, Vol. 47, No. 3 7 8 7 -3 7 8 8 pages (1 982) [Non-Patent Document 3] Arch. Pharm. Res., Vol. 20, pp. 264-268 (1 997) [Non-Patent Document 4] Bioorg. Med · Chem. Lett ·, Vol. 8 41-46 M (1998) [Non-Patent Document 5] Arch. Pharm · Res ·, Vol. 24, pp. 276-28 0 (200 1) [Non-Patent Document 6] Bioorg · Med. Chem ·, No. Volume 10, 2 95 3-2 96 1 (2002) [Non-Patent Document 7] Tetrahedron Lett ·, Volume 45, 2 763-2 766 (2004) [Non-Patent Document 8] J. Org · Chem ·, Vol. 69, Page 2 76 8-2772 (2004) [Summary of the Invention] -7- 200536830 (3) The present invention is to provide a treatment and a therapeutic agent having high antitumor activity and effective against proliferative diseases such as cancer and Compounds for preventive agents and their manufacture , In the manufacture of useful intermediate compounds, and pharmaceutical compositions containing these compounds for the purpose. The present inventors have conducted detailed investigations for the purpose of providing novel therapeutic and preventive agents effective against proliferative diseases such as cancer, and found that the compounds of the present invention have excellent antitumor activity, and completed the present invention. That is, one of the inventions of the present invention is that the present invention provides a compound represented by formula (1), a prodrug thereof, or pharmaceutically acceptable salts thereof, characterized in that the compound is represented by formula ya1

(4) (4) 200536830 Atom, 8 alkyl, aryl Cl-6 alkyl, aryl and heteroaryl substituted with substituents, C2-7 alkynyl (the c I 7 alkynyl may be The above is selected from halogen atoms, C] -8 alkyl, aryl c] -6 alkyl, aryl and heteroaryl substituted by substituents), halogen atoms, hydroxyl, aryl, heteroaryl, cyano, amine (The amine group can be substituted by 1 or 2 selected from Cl-8 alkyl, aryl, aryl c which may be substituted by one OR11 or one NR R] -6 alkyl and heteroaryl based on the nitrogen atom Substitute), S (〇) llRl4 (where η is not an integer of 0 ~ 2), Ci ~ 6 alkoxy (the alkoxy group may be selected from aryl, heteroaryl, 1 or more,- 〇Rll, —nr12r13 and halogen atom substituted), 4 to 7-membered heterocyclic group (the heterocyclic group may be substituted by 1 or more substituents selected from the D group), aryloxy, heteroaryl Formed by an alkoxy group and Cl-6 alkylene dioxy group; wherein, R1], R12, R13, and Rl4 are independently selected from a hydrogen atom, C] -8 (the academy may be selected from 1 or more than 1 From halogen atom, hydroxyl, c 1-6 alkoxy Amino group, C〗 -6 alkylamino group, diC] -6 alkylamino group, substituted with aryl and heteroaryl substituents), aryl and heteroaryl; or R 1 2 and R 13 may It is connected to the bonded nitrogen atom to form a 4- to 7-membered heterocyclic ring containing at least one nitrogen atom; R1 represents a C 1-8 compound which may be substituted by 1 or more substituents selected from a hydrogen atom or a B group ; R2 represents C which may be substituted by 1 or more substituents selected from the B group] -8 alkyl, —COOR3, ~ coR4, —COSR5, —CONR6R7, —NR22R23, or —N = CR24r25; or R] And r2 may be connected to the nitrogen atom to be bonded to form a 4 to 10-membered heterocyclic ring containing at least 丨 nitrogen atoms (-9- (5) 200536830 This heterocyclic ring may be selected from the C group% 1 or more ^ 3 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — There ’’ ’ve been better to say From halogen atom, chemotactic group, c I-6 alkyloxy group (the alkoxy group t "is substituted by 1 or more substituted hydroxy groups, C] -6 alkoxy groups and phenyl groups substituted with phenyl groups, C3 -8 cycloalkyl,

Aryl and heteroaryl substituents A ^, C3-8 cycloalkyl, aryl or heteroaryl;

R4 represents a C! -8 alkyl group, an aryl group, and a heteroaryl group which may be substituted by a hydrogen atom and may be substituted by R2G of W 1 or 1; R5 represents a hydrogen atom, a C group; And heteroaryl; R2 ° represents a mesogen, a prime atom, an aryl group, a heteroaryl group, and a Cl-6 group oxygen group (the group oxygen group can be selected from halogen atoms, aryl groups, and heteroaryl groups by 1 or more) Substituted by a substituent), aryloxy, heteroaryloxy, amine (the amine group represents that can be selected from Ci-8 alkyl, aryl, aryl Ci 6 alkyl, hetero square and- COOR2] substitution is based on substitution on the nitrogen atom) or a 4- to 7-membered heterocyclic group containing at least] nitrogen atoms (the heterocyclic group may be substituted by C] -8 alkyl groups); R21 represents C] i alkyl , Aryl c] -6 alkyl or aryl; R and R represent independently selected from a chlorine atom, Cl-8 alkyl, aryl and heteroaryl; R and 11 represent independently selected from a hydrogen atom, (^ -8 alkyl , Aryl and heteroaryl; R and R represent independently selected from a hydrogen atom, C] -8 alkyl, aryl and heteroaryl; -10- 200536830 (6) Group B represents a halogen atom, C] -6 alkane Carbonyl, c6 alkylaminocarbonyl, Ci-6 Aryl group, aryl group (this aryl table cannot be selected from 1 or more than halogen atom, Ci-8 alkyl group, C ^ -8 haloalkyl group, hydroxyl group, Cn alkoxy group and C! -6 haloalkoxy group Substituted by a substituent), heteroaryl, —OR31, and NR32R33; wherein R31, R32, and R33 represent independently selected from a hydrogen atom and a Cl_8 alkyl group (the alkyl group may be selected from 1 or more than halogen Atom, hydroxy, Ci-6 ® alkoxy, aryl, amine, C! -6 alkylamino and dic! -6 alkylamino substituents), aryl, heteroaryl and -COOR34; R34 represents a C] -8 alkyl group, an aryl Cl-6 alkyl group or an aryl group; or R3 2 and R33 may be bonded to the nitrogen atom to be bonded to form a 4-7 member heterocyclic ring containing at least one nitrogen atom (The heterocyclic group may be substituted by 1 or more groups selected from the group D); Group C represents an aryl group, a heteroaryl group, a 6 alkylcarbonyl group, a C! -6 alkylamino group M, C] 1 alkoxycarbonyl, hydroxy, C 1-8 alkyl, C -6 alkoxy • * (1 ^ endyl and alkoxy represent 1 or 1 or more selected from halogen atoms, aryl, heteroaryl, -NR4lR42 and -0r43 are substituted), aromatic Formed by an alkoxy group and a heteroaryloxy group; wherein 'R41, R42, and R43 represent independently selected from a hydrogen atom, a Cl_8 alkyl group (1 ^ complete group_, which can be selected from 1 or 1 selected from a halogen atom, a hydroxyl group, and C! — 6 fired ^ ^ 'amino, C-6 alkylamine, and di-C] -6 alkylamine substituents;), aryl Cl-6 alkyl, aryl and heteroaryl; or r41 &amp; K42 can be bonded to the bonded nitrogen atom to form at least! 4 to 7-membered heterocyclic ring of each nitrogen atom; -11-200536830 (7) D group represents a group selected from halogen atom, aryl group, heteroaryl group, aryloxy group, heteroaryloxy group, and amine group (the amine group may be 1 or 2 selected from C! -8 alkyl, hydroxy C! -6 alkyl, c! -6 alkyloxy C 1-6 alkyl, C 1-6 alkyl amino C] -6-alkane Group, diCl_6 alkylamino group C] -6 alkyl group, aryl group, aryl Ci-6 alkyl group and heteroaryl group are substituted based on nitrogen atom substitution), hydroxyl group, C! -6 alkoxy group (the Alkoxy means that it may be substituted by 1 or more substituents selected from halogen atoms, hydroxyl groups, Ci-6 alkoxy groups, Ci-6 alkylamino groups and di-C] -6 alkylamino groups), C 1 _ 6 alkoxycarbonyl group, c!-8 alkyl group (the table of this hospital can not be selected from 1 or more than 1 selected from the halogen atom, meridian, Ci-6 alkoxy group, C] -6 alkoxycarbonyl group, amine Group, aryl group, heteroaryl group, c] -6 amine group and di C! -6 alkylamino group (substituted by substituents))]. Another invention of the present invention is to provide a compound of formula (1) above, a prodrug thereof, or these salts which are pharmaceutically acceptable, wherein Y3 represents ~ NR! R2. Another invention of the present invention is to provide a formula as described above ( 1) of compounds, which drive drugs, or pharmaceutically acceptable salts, wherein γ1, γ2, and γ4 represent hydrogen atoms, Υ3 represents -nWr2; X represents an aryl or heteroaryl group, and the aryl group may be The above is substituted by a substituent selected from Group A; Group A represents a C! -8 alkyl group (the alkyl group may be substituted by 1 or more substituents selected from halogen atoms and -NR 12 R 13), halogen atoms, hydroxyl groups , Square group, amine group (the amine group is optional; 1 or 2 selected from the group consisting of 8 alkyl-12- 200536830 (8) and aryl substitution based on the nitrogen atom up to the lamp), SR14, Cj- 6 alkoxy group (the alkoxy group may be substituted by 1 or 1 or more substituents selected from an OR11 and a halogen atom), 4 to 7-membered heterocyclic groups (the heterocyclic group may be selected from 1 or 2 selected from C! -8 alkyl and C ^ -6 alkoxycarbonyl substitutions are based on substitution on the nitrogen atom; where Ri1, Ri2 ', R13 and R14 represent independently selected A hydrogen atom, a C! -8 alkyl group, and an aryl group; or R12 and R13 may be connected to the nitrogen atom to be bonded to form a 4- to 7-membered heterocyclic ring containing at least one nitrogen atom; R1 means that it can be selected from 1 or 1 or more C! -8 alkyl substituted by a hydrogen atom or a substituent of group B; R2 represents a C! -8 alkyl group which may be substituted by 1 or more substituents selected from group B, -COOR3, -COR4,- COSR5, —CONR6R7, —NR22R23, or —N—CR24R25; or R1 and R2 can be connected to the nitrogen atom to be bonded to form a 4 to 10-membered heterocyclic ring containing at least one nitrogen atom (the heterocyclic ring can be 1 or more than 1 Selected from the substituents of the C group); wherein R3 represents a C ^ -8 alkyl group (the alkyl group may be selected from 1 or more than a halogen atom, a hydroxyl group 'C! -6 alkoxy group (the alkoxy group may be 1 or more is selected from the group consisting of a substituent substituted with a phenyl group, a C 1-6 alkoxy group and a phenyl group), a c3-8 cycloalkyl group, an aryl group and a heteroaryl group with a substituent group), a C2-7 ene Group, C2-7 alkynyl group, C3-8 cycloalkyl group, aryl group or heteroaryl group; R4 represents a C! -8 alkyl group, an aryl group and a heterocyclic group selected from a hydrogen atom and may be substituted by 1 or more R2G Aryl; R5 means selected from alkane And aryl groups; R2G represents a hydroxyl group, a halogen atom, an aryl group, a heteroaryl group 'C! -6 alkoxy-13- 200536830 (9), an aryloxy group, an aryl group] -6 alkoxy group, an amine group ( The amine group means that one or two substituents selected from the group consisting of C! -8 alkyl, aryl, and ~ c00R2] may be substituted based on nitrogen atoms) or 4 to 7 members containing at least one nitrogen atom. A cyclic group (the heterocyclic group may be substituted by a C] -8 alkyl group); R21 represents a Ci-8 alkyl group, an arylalkyl group or an aryl group; R6 and R7 represent independently selected from a hydrogen atom, a Ci-s alkyl group, and Aryl; R22, R 23, R24, and R2 5 represent independently selected from a hydrogen atom, C 1-8 alkyl, aryl and heteroaryl group> Group B represents a halogen atom, C 1-6 alkylcarbonyl, aryl , OR31 and —NR32 R3 3; where R31, R 32 and R 33 represent independently selected from hydrogen atoms, C 1-8 courtyard, aryl C: 1-6 courtyard, aryl, heteroaryl And-COOR34; R34 represents a C ??-8 alkyl group, an aryl C] -6 alkyl group or an aryl group, or R32 and R33 may be bonded to a nitrogen atom to be bonded to form 4 to 4 containing at least one nitrogen atom. 7-membered heterocyclic ring; C group table (:! -6 alkylcarbonyl, hydroxy, Ci-8 alkyl, aryl Cl-6 alkoxy Ci-8 alkyl, hydroxy C] -8 alkyl, aryloxy and heteroaryloxy. Another invention of the present invention is to provide a compound of formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof, in which R2 is bonded to the nitrogen atom to be bonded to form a compound containing at least one nitrogen atom. A 4- to 10-membered heterocyclic ring, which may have a substituent selected from the group C. Another invention of the present invention is to provide the compound of formula (1) as described above, a prodrug thereof, or pharmaceutically acceptable salts thereof, wherein γ 2 or γ 3 is -14- (10) 200536830 morpholinyl, aza Cyclobutane, pyrrolyl or piperidinyl, the heterocyclic group may be substituted by 1 or more substituents selected from the group consisting of hydroxy or hydroxy c! -6 alkyl. Another invention of the present invention is to provide a compound of formula (1), a prodrug thereof, or these salts which are pharmaceutically acceptable, wherein Y2 or Y3 is morpholinyl, azetidine, pyrrolyl, 3- Hydroxypyrrolyl, 2-hydroxymethylpyrrolyl, 3-hydroxymethylpyrrolyl, piperidinyl, 3-hydroxypiperidinyl, 4-monohydroxypiperidinyl, 2-hydroxymethylpiperidinyl, 3- Hydroxymethyl piperidinyl, 4-hydroxymethylpiperidinyl, or 4-hydroxy-4 4-hydroxymethylpiperidinyl. Another invention of the present invention is to provide the compound of formula (1) above, a prodrug thereof, or these salts which are pharmaceutically acceptable, wherein R] is a hydrogen atom or a C8 alkyl group (the alkyl group may be 1 or 1 The above is substituted by a substituent selected from the B group); R2 is a ci-8 alkyl group, a COOR3 or -COCH2NHCOOR21 substituted by 1 or more substituents selected from the B group. # Another invention of the present invention is to provide the compound of formula (1) above, a prodrug thereof, or these salts which are pharmaceutically acceptable, wherein R1 is a hydrogen atom; R2 is ~ COOR3, -COSR5, -CONR6R7 or -c 〇R4. Another invention of the present invention is to provide a compound of formula (1), a prodrug thereof, or these salts which are pharmaceutically acceptable, wherein R 2 is a C 〇 〇 3 〇 Another invention of the present invention is to provide as above A compound of formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof, in which R3 is C! -15-200536830 (11) courtyard, C 2-7 alkenyl, C 2-7 alkynyl, the The base, storage group and alkynyl group can be selected from 1 or 1 selected from the group consisting of a halogen atom, meridian group, and Ci-6 compound oxygen (the compound is selected from 1 or 1 or more selected from a hydroxyl group, a C! -6 alkoxy group And phenyl substituents). Another invention of the present invention is to provide a compound of formula (1) above, a prodrug thereof, or these salts which are pharmaceutically acceptable, wherein R3 is a C! -8 alkyl group substituted by a hydroxyl group of 1 or more, A C2-7 alkenyl group substituted by a hydroxyl group of 1 or more, or a C2-7 alkynyl group substituted by a hydroxyl group of 1 or more. Another invention of the present invention is to provide the compound of formula (1), a prodrug thereof, or these salts which are pharmaceutically acceptable, wherein R3 is a C! -6 alkyl group substituted by a hydroxyl group of 1 or more. Another invention of the present invention is to provide a compound of formula (1), a prodrug thereof, or these salts which are pharmaceutically acceptable, wherein γ2 or Y3 is a bis (hydroxyC! -6 alkyl) amino group, a methyl group (Hydroxy C! -6 alkyl) amino group, mesyl C 1-6 alkyl amino group, methyl (manganyl C 1-6 alkyl group) amino group, amino group C] -6 alkyl amino group, C! — 6 alkoxycarbonylamino, or hydroxyl C 1-6 alkoxycarbonylamino. Another invention of the present invention is to provide the compound of formula (1), a prodrug thereof, or these salts which are pharmaceutically acceptable, wherein Υ2 or Y3 is a bis (2-hydroxyethyl) amino group, a methyl group (2 —Hydroxyethyl) amino, 2-monohydroxyethylamino, methyl (2-morpholine-4-ylethyl) amino, methyl (2-aminoethyl) amino, or 2-hydroxyethyl Oxycarbonylamino. Another invention of the present invention is to provide the compound of formula (1) as described above, -16-200536830 (12) a prodrug thereof, or pharmaceutically acceptable salts thereof, wherein X is phenyl or heteroaryl, and the phenyl Or the heteroaryl group may be substituted with 1 or more substituents selected from the group A. Another invention of the present invention is to provide the compound of formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein X is a phenyl group, and the phenyl group may be substituted by 1 or more selected from the group A Group. Another invention of the present invention is to provide a compound of formula (1), B, a prodrug thereof, or pharmaceutically acceptable salts thereof, wherein x is phenyl or heteroaryl, and the phenyl or heteroaryl is 1 or 1 or more substituted with a substituent selected from Group A; Group A is C substituted with 1 or more halogen atoms] -8 alkyl, aryl, C-6 alkylthio, di-C 1-6 alkylamino, 4- to 7-membered heterocyclic groups containing at least one nitrogen atom, C! -8 alkyl, C2-7 alkenyl, C2-7 alkynyl, C! -6 alkoxy ( The alkoxy group may be substituted by a halogen atom of 1 or more) and a hydroxyl group. Another invention of the present invention is to provide a compound of the formula (1) as described above, a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein X represents a phenyl group, and the phenyl group can be selected from at least two ethyl groups, Substituted by substituents of trifluoromethyl, trifluoromethoxy, methylthio, methoxy, chloro, phenyl, dimethylamino, morpholinyl, pyrrolyl, and piperidinyl. Another invention of the present invention is to provide a compound 'which is a compound represented by Formula W; -17- (13) 200536830

IV (In the formula, X represents a phenyl group or a heteroaryl group, and the phenyl or heteroaryl group may be substituted by 1 or more substituents selected from the group A; L represents a bond on the isoD quinolinone ring The halogen atom at the 6 or 7 position. ^ Another aspect of the present invention is to provide a method for producing a compound of the formula (1) as described above, which is an amination step containing a compound of the formula JV. Another invention of the present invention In order to provide a method for producing the compound of the above formula (1), the method contains a compound of the formula IV in an appropriate solvent (for example, toluene, THF, 1,4-dioxane, xylene, dimethoxyethane, etc.), and appropriate f. Catalysts such as Pd (〇Ac) 2, Pd2dba3,

PdCl2 [P (o— tol) 3] 2 &gt; Pd (02CCF3) 2 etc.), ligands (for example, P (o-tol) 3, BINAP, DPPD, P (t-Bu) 3, 2 φ — Dicyclohexylphosphino- 2 / — (N, N-dimethylamino) bisphenyl, 2-(dicyclohexylphosphino) bisphenyl, etc.), and bases (for example, t — BuONa, LiHMDS, Cs2C03 , K3PO4, etc.), a step of reacting with an appropriate amine. Another invention of the present invention is to provide a pharmaceutical composition, which is a compound of the above formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Another invention of the present invention is to provide a therapeutic and preventive agent for malignant tumors, which is a compound of the above formula (1), a prodrug thereof, or a salt of -18- (14) 200536830 which is permitted in medicine. As an active ingredient. Among them, malignant body cancer. Embodiments of the invention The "aryl group" in the present invention means a fragrant square having 6 to 10 carbon atoms, such as containing a phenyl group, a 1- (L) group, a 2- (L) group, and the like. The "heteroaryl group" in the present invention means 5 to 5 fragrant squares containing one or more heteroatoms of nitrogen, nitrogen, and sulfur atoms. For example, it contains furyl, thienyl, pyrilyl, imidyl, Pyridazolyl, isoxazolyl, thiazolyl, isothiazolyl, spirodi-11ylyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, fluorinyl , Isoquinolinyl. The "halogen atom" in the present invention means a fluorine atom, a chlorine atom, an iodine atom, and the like. Examples of preferred halogen atoms include fluorine. The "¢ ^ -8 alkyl group" of the present invention represents a linear alkyl group having 1 to 8 carbon atoms, and contains, for example, methyl, ethyl, n-propyl, and isobutyl. Base, second butyl, isobutyl, third butyl, n-pentyl, butyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, pentyl, 3-ethylbutyl, and 2-ethylbutyl. Examples of the C! -8 alkyl group include a linear or branched C! -8 alkyl group which is a linear or branched Ci-6 alkyl group. The "C3-8 cycloalkyl group" in the present invention means a cyclic alkyl group having 3 to 8 carbon atoms. For example, a cycloalkyl group, a cyclobutyl group, and a cyclopentane tumor are solid hydrocarbon groups. , Azolyl, oxa, thiadiazole, pyridazinyl, bromine atom. Chain or branched propyl group, n-methyl group, n-hexyl 1-methyl group, more preferable cyclic and partial group, cyclohex-19- (15) (15) 200536830 group, cycloheptyl group, ring Octyl, methylcyclopropyl, cyclopropylmethyl and cyclohexylmethyl. The "C2-7 alkyl group" in the present invention means a linear or branched alkenyl group having 2 to 7 carbon atoms, for example, containing vinyl (vinyl), 1-propenyl, 2-propenyl (allyl) , Allyl 2-alkenyl, 3-butenyl (high allyl) and the like. The "C2-7 alkynyl group" in the present invention means a straight or branched chain alkynyl group having 2 to 7 carbon atoms, and for example, contains ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. The "C! -6 alkoxy group" in the present invention means a linear or branched alkyl group having an alkyl portion of 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group having 3 to 6 carbon atoms.之 alkoxy. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy, isobutoxy, third butoxy, n-pentyloxy, 3- Methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentyloxy, 1-methylpentyloxy, 3-ethylbutoxy, and 2-ethylbutoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyl Oxy, cyclopropylmethoxy, etc. The "aryloxy group" in the present invention means an aryloxy group having an aromatic hydrocarbon group having 6 to 10 carbon atoms as a defined aryl group. For example, it contains a phenoxy group, a 1- (L) yloxy group, and a 2- (L) yloxy group. The "heteroaryloxy group" in the present invention means that the heteroaryl moiety is a 5- to 10-membered aromatic heterocyclic ring having one or more defined heteroatoms selected from oxygen, nitrogen, and sulfur atoms. Heteroaryloxy groups such as furan-20- 200536830 (16) oxy, thienyloxy, pyrrolyloxy, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyloxy Methyl, isothiazolyloxy, oxadiazolyloxy, thiadiazolyloxy, triazolyloxy, tetrazolyloxy, pyridyloxy, pyrimidinyloxy, pyrazinyloxy, pyridazinyloxy, indolyloxy Group, quinolinyloxy, isoquinolinyloxy.

The "c] -6 haloalkyl group of the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms as the alkyl moiety, and having cyclic and partially cyclic alkyl groups having 3 to 6 carbon atoms. , An alkyl group substituted with one or more halogen atoms. For example containing trifluoromethyl, trichloromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trichloroethyl, bromomethyl, di Bromomethyl, tribromomethyl, iodomethyl, difluoromethyl, and dichloromethyl. The "C] -6 haloalkoxy group of the present invention means a linear or branched alkane having 1 to 6 carbon atoms as the alkyl moiety, and a cyclic and partially cyclic alkane having 3 to 6 carbon atoms. Is an alkoxy group substituted by one or more halogen atoms. For example containing trifluoromethoxy, trichloromethoxy, chlorodifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2,2,2-trichloroethoxy , Bromomethoxy, dibromomethoxy, tribromomethoxy, iodomethoxy, difluoromethoxy, and dichloromethoxy. The "C] -6 alkylamino group of the present invention means a linear or branched alkane having 1 to 6 carbon atoms as the alkyl moiety, and a cyclic and partially cyclic alkane having 3 to 6 carbon atoms. Alkylamino groups, such as methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, second butylamine, isobutylamine, third butylamine, n-pentylamine Base, 3-methylbutylamino, 2-methylbutylamino, 1-methylbutylamino, 1-ethylpropylamino, and n-hexylamino, 4-monomethyl-21-(17) (17 ) 200536830 pentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3-ethylbutylamino and 2-ethylbutylamino. The "di-C! -6 alkylamino group" of the present invention means a straight or branched chain having 1 to 6 carbon atoms as two alkyl moieties and having a cyclic and partial ring having 3 to 6 carbon atoms. A dialkylamino group of an alkyl group, the two alkyl moieties are the same or different, and the "diC! -6 alkylamino group" contains, for example, a dimethylamino group, a diethylamino group, and a dialkylamino group. N-propylamine, di-n-propylamine, di-isopropylamine, di-n-butylamine, methyl-n-butylamine, methyl second-butylamine, methyl-isobutylamine, methyl tertiary butylamine Group, ethyl n-butylamino group, ethyl second butylamino group, ethyl isobutylamino group, ethyl tertiary butylamino group, and the like. The "C 6 alkylcarbonyl group" in the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms as the alkyl moiety, and a cyclic and partially cyclic alkyl group having 3 to 6 carbon atoms. Carbonyl. The "C! -6 alkylaminocarbonyl" of the present invention means a linear or branched chain having 1 to 6 carbon atoms as the alkyl moiety, and having a cyclic and partially cyclic carbon number of 3 to 6 Alkylalkylaminocarbonyl. The "amine C ^ -6 alkoxycarbonyl group" in the present invention means a straight or branched chain having 1 to 6 carbon atoms as the alkoxy moiety, and having a cyclic and partial ring having 3 to 6 carbon atoms. The amine group of the alkoxy group is an oxo group. The "hydroxyC] -6 alkyl group of the present invention means a linear or branched chain having 1 to 6 carbon atoms as the alkyl moiety, and a cyclic or partially cyclic alkyl group having 3 to 6 carbon atoms. By the base of the courtyard. The "CI-6 thiol thio group" in the present invention indicates that the base portion is a linear or branched chain having 1 to 6 carbon atoms, and has a ring and a portion having 3 to 6 carbon atoms. (18) (18) 200536830 parts of cyclic alkyl alkylthio groups, such as containing methylthio, ethylthio, n-propylthio, isopropylthio, n-butyl Methylthio, second butylthio, isobutylthio, isobutylthio, third butylthio, n-pentylthio, 3-methylbutylthio , 2-methylbutylthio, 1-methylbutylthio, 1-ethylpropylthio, n-hexylthio, 4-methylpentylthio, 3-methyl Pentylthio, 2-methylpentylthio, 1-methylpentylthio, 3-ethylbutylthio, 2-ethylbutylthio and the like. The "aryl C! -6 alkyl group" of the present invention is a linear or 6-carbon aromatic hydrocarbon group having a defined carbon number of 6 to 10 as the aryl moiety and a linear or 1 to 6 carbon number as the alkyl moiety. An aralkyl group which is branched and has a cyclic and partially cyclic alkyl group having 3 to 6 carbon atoms, for example, contains a benzyl group, a 1-phenethyl group, a 2-phenethyl group, and the like. The "4- to 7-membered heterocyclic ring containing at least one nitrogen atom" in the present invention means that it contains one or more nitrogen atoms, and the other contains one or more heteroatoms selected from oxygen and sulfur atoms, or in a ring. The saturated or unsaturated heterocyclic ring containing 4 to 7 atoms also includes aromatic heterocyclic rings. Among them, the sulfur atom contained in the ring can also be oxidized to form S (0) n (η = 1 or 2). Specific examples include azetidinyl, pyrrolidine, piperidine, piperazine, pyrrole, imidazole, imidazoline, pyrazole, pyrazoline, oxazoline, morpholine, thiomorpholine, and oxothio Morpholine, dioxothiomorpholine, pyridine, pyrazine, pyrimidine, pyridoxine, hexamethyleneimine, octahydroisoquinoline and the like. The "4- to 7-membered heterocyclic group containing at least one nitrogen atom" in the present invention means that it contains 1 or more nitrogen atoms, and the other contains 1 or more -23- (19) (19) 200536830 selected from oxygen A hetero atom of an atom and a sulfur atom, or a saturated or unsaturated heterocyclic group having 3 to 7 atoms in the ring. Among them, the sulfur atom contained in the ring can also be oxidized to form S (Ο) n (η = 1 or 2). The heterocyclic group may have a monocyclic, condensed ring or spiro ring skeleton, or an aromatic heterocyclic group. Specifically, it contains, for example, azetidinyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxazoline, morpholinyl, Thiomorpholinyl, oxythiomorpholinyl, dioxothiomorpholinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridoxyl, hexamethylimino, octahydroisoquinolinyl, etc. . The substitution position of the heterocyclic group is only a substitutable position on a carbon atom or a nitrogen atom, and is not particularly limited. The "4- to 7-membered heterocyclic group" according to the present invention means that it may contain one or more heteroatoms or heteromolecules selected from nitrogen, oxygen, and sulfur atoms, and the number of atoms contained in the ring may be saturated from 4 to 7. Or unsaturated heterocyclic ring, also contains aromatic heterocyclic ring. Among them, the sulfur atom contained in the ring can also be oxidized to form S (0) n (n = i or 2). Specific examples include azetidinyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxazoline, morpholinyl, Thiomorpholinyl, oxythiomorpholinyl, dioxothiomorpholinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridyl, hexamethylimino, furanyl, tetrahydrofuranyl, thiophene Radicals, tetrakis (hydroxyphenyl), -oxopentan, Oxathiolanyl, Dioxanyl, etc. The substitution position of the heterocyclic group is only a substitutable position on a carbon atom or a nitrogen atom, and is not particularly limited. The "4- to 10-membered heterocyclic ring containing at least one nitrogen atom" in the present invention means that it contains one or more nitrogen atoms, and the other contains one or more nitrogen atoms. • 24- (20) (20)

200536830 A heteroatom from an oxygen atom and a sulfur atom, or a saturated or unsaturated heterocyclic ring containing 10 atoms in the ring, which also includes an aromatic heterocyclic ring, a bicyclic heterocyclic ring and a spirocyclic skeleton. Among them, this atom can also be oxidized to form S (0) n (n = 1 or 2). Examples include azetidinyl, pyrrolidine, piperidine, piperazine, pyridine, imidazoline, pyrazole, pyrazoline, oxazoline, morpholine, thiothiomorpholine, dioxothio Morpholine, pyridine, pyrazine, pyrimidine, dimethylimine, decahydroquinoline, decahydroisoquinoline, indole, and eight heterocyclic groups containing a spiro ring skeleton contain the following formula: The number is 3 ~ or Examples of condensed sulfur-containing protozoa, imidazomorph, oxaloxazole, hexahydroindole, etc.

Illustrated heterocyclic heterocyclic groups and the like. In the present invention, "an S (O) nR14" means an SR14, or ~ S02R14, for example, it contains an S (O) n (C ??-6 alkyl), ~ S (0) n (aryl), -S (0) n (heteroaryl). Specific examples of "mono-S (0) nR14" include methylthio, methyl, n-propylthio, isopropylthio, trifluoromethylthiomethylthio, 4-methylbenzene Methylthio, phenylthiosulfofluorenyl, ethylsulfinamilide, n-propylsulfinamilide, isopropyl, trifluoromethylsulfinamido, benzylsulfinamido, 4-sulfinyl sulfenyl, phenylsulfinyl sulfonyl, methylsulfonyl sulfonyl, ethylsulfonylsulfonyl sulfonyl, isopropylsulfonyl sulfonyl, trifluoromethylsulfonyl sulfonyl, monoSOR1 ethylthio Substituents, benzene, methylidenesulfinylmethylphenylfluorenyl, n-benzylsulfonyl 25-200536830 (21) fluorenyl, 4-methylphenylphenyl fluorenyl, and phenyl醯 基 et al. In the present invention, "C] -6 alkylene dioxy group means a linear or branched alkylene group having 1 to 6 carbon atoms, and a divalent group" one 0 "is bonded to an adjacent carbon atom. -(C! -6 alkylene) -10- ", for example containing alkylene dioxy, ethylene dioxy, methyl methyl dioxy, dimethyl methyl dioxy, etc. . In this specification, when an arbitrary group is substituted with 1 or more substituents, the substituents may be the same or different, and the number of substituents may be from 1 to the maximum number that can be substituted in the chemical structure. The number of substituents may be, for example, 1 to 7, typically 1 to 5, and particularly 1 to 3. The present invention is a pharmaceutically acceptable salt containing a salt of a compound represented by the formula (1) and a prodrug of the compound. These salts are produced by contacting the compound or a prodrug of the compound with an acid or a base usable in the manufacture of pharmaceuticals. The salt contains carboxylic acids such as hydrochloride, hydrobromide, hydroiodate, sulfate, sulfonate, phosphate, phosphonate, acetate, citrate, malate, and salicylate. Salt, or alkali metal salt such as sodium salt, potassium salt; alkaline earth metal salt such as magnesium salt, calcium salt; ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc. Ammonium salts, etc. The "prodrug" of the present invention is a derivative of a compound of formula (1) which is converted to a compound of formula (1) or a pharmaceutically acceptable salt of these salts under physiological conditions. Prodrugs also include compounds of formula (i) that can be converted to be inactive when administered to a patient, but are active in vivo. In the compound represented by formula (1) of the present invention, X is a phenyl group which may be substituted -26- 200536830 (22), and also contains the following formula:

〇

As the compounds shown, specific examples of the present invention include compounds not shown in Table 1 below. However, the present invention is not limited to these listed compounds. And the numbers in the table are indicated with the corresponding compound names. In the following table, "Me" represents a methyl group, "Et" represents an ethyl group, "1-Bu" represents a third butyl group, and "*" represents a bonding site.

-27- 200536830 (23) [Table 1]

Compound number R 1 a R2a R3a R5e y1 Y2 Example 1 cf3 HHHHHC] Example 1 Step B 2 Η HHHHH Cl Example 2 3 ocf3 HHHHH Cl Example 3 4 cf3 HHHHH CN- * Example 4 5 HHHHHH 〇- ★ Example Example 5 6 〇cf3 HHHHH Example 6 7 cf3 HHHHH / ~ \ 0 \ _Λ * Example 7 8 HHHHHH / ~ \ 〇V __ / N-* Example 8 9 〇cf3 HHHHH / ~ \ ° \ _ / N ~ * Example 9 10 cf3 HHHHH 〇- * Example 1 〇11 HHHHHH 〇- * Example 1 1 12 〇cf3 HHHHH 〇- * Example 1 2 13 HHHHHH / &quot; \ Me-NN- * V_ / Example 1 3 14 HHHHHH O-Me Example 1 4 1 5 HHHHHHH Example 1 15 16 0cf3 HHHHHH Example 1 6 17 HHHHHH Me Example 1 7 -28- (24) 200536830

18 0CF3 HHHHH Me Example 1 8 19 cf3 HHHHH Me Example 1 9 2 0 cf3 HHHHH HM &gt; Example 2 0 2 1 HHHHHH HM &gt; Example 2 1 2 2 〇cf3 HHHHHH HCK &gt; Example 2 2 2 3Hcf3 HH Example 2 3 2 4 HHHHHH ho Eight Example 2 4 2 5 〇cf3 HHHHH HO Eight Example 2 5 2 6 cf3 HHHHH, 0H Example 2 6 2 7 HHHHHH rT Example 2 7 2 8 〇cf3 HHHHH / -T 〇H \ _yN_ * Example 2 8 2 9 cf3 HHHHH HO-<) N_ * Example 2 9 3 0 HHHHHH Example 3 0 3 1 0CF3 HHHHH HO-<) N- * Example 3 1 3 2 cf3 HHHHH ΗΟχτ * Example 3 2 -29- (25) 200536830

3 3 HHHHHHH 0 &quot; Example 3 3 3 4 ocf3 HHHHHH 0 &quot; CT * Example 3 4 3 5 cf3 HHHHH Example 3 5 3 6 HHHHHH HO 乂) r * Example 3 6 3 7 0CF3 HHHHH Implementation Example 3 7 3 8 cf3 HHHHH nh2 Example 3 8 3 9 HHHHHH nh2 Example 3 9 4 0 0CF3 HHHHH nh2 Example 4 0 4 1 A cf3 HHHHHJ ~ \ HO N— ★ H Example 4 1 4 1 B cf3 HHHHH HO N ~ \ N One * / ^ / HO Example 4 1 4 2 AHHHHHH / ~ \ HO N— * H CF3COOH Example 4 2 4 2 BHHHHHH HO N ^ \ N One * J ^ 'HO Example 4 2 4 3 A 〇cf3 HHHHH Jr ~ \ HO N- * H Example 4 3 4 3 B 〇cf3 HHHHH HO // HO Example 4 3 4 4 AHHHHHH / ™ \ MeO N— * H Example 4 4 4 4 BHHHHHH MeO N- * / -7 MeO Example 4 4 4 5 HHHHHHH OH H Example 4 5 -30- 200536830 (26)

4 6 Η Η Η Η Η HOΟ HO j Ν ~ * / 7 ΗΟ Example 4 6 4 7 cf3 Η Η Η Η ^ / ^ \ Η〇, N— * Me Example 4 7 4 8 Η Η Η Η Η Η Η / ~ \ HO Ν- * Me Example 4 8 4 9 ocf3 Η Η Η Η \ / \ HO Ν- * Me Example 4 9 5 0 Η Η Η Η Η Η Η〇 八 丫 八 OH Me Example 5 0 5 1 Η Η Η Η Η OH OH Me Example 5 1 5 2 〇CF3 Η Η Η Η Me 0 Me Example 5 2 5 3 〇cf3 Η Η Η Η η2ν, ^ ν / * Me 2CF3COOH Example 5 3 5 4 Η Η Η Η Η η2ν, ^ ν / * Η 2CF3COOH Example 5 4 5 5 Η Η Η Η Η Me Example 5 5 5 6 Η Η Η Η Η CF Me CF3COOH Example 5 6 5 7 Η Η Η Η Η Η c 丨 Η Example 5 7 5 8 Η Η Η Η Η Η Me0 ^ V * Η Example 5 8 5 9 Η Η Η Η Η Η α. People * Example 5 9 6 0 Η Η Η Η Η Η Η Η Example 6 0 -31-(27) 200536830 (27)

6 1 cf3 Η Η Η Η Η Λ ^ Η0 Κ Example 6 1 6 2 Η Η Η Η Η Η X / Β〇κ Example 6 2 6 3 Η Η Η Η Η Η Η 9 丫丫 ν ^ Λν / 0实施 Example 6 3 6 4 Η Η Η Η Η η η2ν ^ Λν, Η CF3COOH Example 6 4 6 5 Η Η Η Η Η d Η Η Example 6 5 6 6 Η Η Η Η Η Η Me2N ^ AN〆 * 6 Example 6 6 6 7 Η Η Η Η Η Η Μβ 、 ΓΜ Η Example 6 7 6 8 Η Η Η Η ~ / ~ \ 0 Ν- * Η Example 6 8 Step C

-32- (28) 200536830 The following are the compound names corresponding to the above compound numbers. (I): 7-chloro-3- (2-trifluoromethylphenyl)-2H-iso-D-quinine-1, 1 (2): 7-chloro-3-phenyl-2H-iso-D-quinine 1-one, (3): 7-chloro-1, 3- (2-trifluoromethoxyphenyl), 2H-isoDquinoline-1, 1-ketone |, (4): 7-pyrrolidine-1 1 mono-3- (2-trifluoromethylphenyl)

)-2H-isoD-quinolin-1-one, (5): 3-phenyl-1-7-0, Brilliantin-1, 1-yl-2H-isoD-quinolin-1, ketone, (6): 7- Pyrrolidine- 1-yl- 3-(2-trifluoromethoxyphenyl)-2H -isoD-Querin-1-1 pay, (7): 7 -morpholine 4 -yl 3-(2- (Trifluoromethylphenyl) —2H —isoD-quinolin-1-one, (8) • 7 —morphine-4 —yl-3 —benzyl-2 Η —isoDquinolin-1 —one, ( 9): 7-morpholine-4-yl-3- (2-trifluoromethoxyphenyl) -2 hydrazone-iso-D-quinine-1-1, (10) ·· 7-piperidine-1 1-1 —3 — (2 —trifluoromethoxyphenyl) — 2 Η —isoD quinine — 1 — 嗣, (II): 3 —benzyl 7 —merbyl — 1 —yl — 2 Η — Isopropyl ketone, (12): 7-piperidine, 1-yl-3, (2-difluoromethoxyphenyl) -2, 1-isopropane-1, -33- (29) 200536830 (13): 7— (4-methyl warm exposure 1-one group) -3—phenyl-2H-isoxantolin-1—one, (14): 7— (benzylmethyl group Amine)-3 -phenyl-2H_ iso-D-quinoline- 1 -one, (15) 7- (2-morpholine-4 monoethylethylamino)-3-phenyl-2H-isoquinoline-1-one, (16): 7 — (2 —morphine-1 4 —Ylethylamino) —3— (2

—Ditrimethoxyphenyl) —2H—isoD-Querin—1—one, (17): 7— [methyl (2-morpholine—4-ylethyl) amino] —3-phenyl —2H —Isoquinoline-1 monoketone, (18): 7- [methyl (2-morpholin-4-ylethyl) amino] —3— (2-trifluoromethoxyphenyl) —2H—Isoquinoline-1 monoone, (19): 7— [methyl (2-morpholine-4-ylethyl) amino] —3— (2-trifluoromethylphenyl) — 2H-isoD-quinoline-1 monoketone, (20): 7- (4-hydroxymethylpiperidine-1-yl) -3- (2-dichloromethylphenyl) -2H-isoquinoline-1 1 monoketone, (21): 7- (4-hydroxymethylpiperidine-1-yl) -3-phenyl-1 2 fluorene-isoD quinine-1 1 fluorene, (22): 7- (4 -1 Hydroxymethylpiperidine- 1-yl)-3-(2 -difluoro / methoxyphenyl)-2 hydrazone-isoD-quinine-1, (23): 7- (3-hydroxymethylpiperone Pyridin-1-yl) -3- (2-trifluoromethylphenyl)-2Η-isoD-quinolin-1-one, (24): 7- (3-hydroxymethylpiperidine-1-yl) 1 3-phenyl-2 fluorene Isoquinine-1, one-pay, -34- (30) 200536830 (25): 7- (3-hydroxymethylpiperidine-1, 1-yl), 3- (2-trifluoromethoxyphenyl) -2H-isoD-quinoline- 1-one, (26): 7-(2-hydroxymethylpiperidine-1 -yl)-3-(2 -trifluoromethylphenyl) -2H-isoD-quinone Porphyrin-1-one, (27): 7- (2-hydroxymethylpiperidine-1 1-yl)-3-phenyl-2 2 hydrazine-isoD-Quulin-1-hydrazone, (28): 7- ( 2-Hydroxymethylpiperidine-1-yl) -3— (2

1-dichloromethoxyphenyl)-2Η-isoD-Quelin-1 1- 嗣, (29): 7 — (4 — kimono group D fixed 1 1-based) — 3 — (2-difluoromethyl Phenyl) -2H-isoquinoline-1 monoketone, (30): 7- (4-hydroxypiperidine-1-1-yl) -3-phenyl-2 isofluorene-1 31): 7 — (4 — 1-yl via hydrazine) — 3 — (2-difluoromethoxyphenyl) — 2Η —isoDquinoline — 1 —one, (32): 7 — (3-1-yl via D-group) —3- (2-difluoromethylphenyl)-2Η-isoD-quinoline-1-one, (33): 7-(3-hydroxypiperidine (1 1 1 base) —3 -phenyl — 2 Η Iso-D is required to pay 1 1 pay, (34): 7 — (3 — 1-based via U-base) — 3-(2 — difluoro (Methoxyphenyl)-2H-isoD-quinolin-1-one, (35): 7-(3-hydroxypyrrolidine-1 -yl) -3-(2 -trifluoromethylphenyl) -2H —Isoquinoline-1, a ketone, (36): 7— (3—Ethyl D] i 1——one—3—phenyl—2 Η IsoD, quinine—1, 35- 200536830 (31) (37): 7 — (3-hydroxypyridine Alkanyl-1 monoyl) -3— (2-trifluoromethoxyphenyl) -2H-isoDquinoline-1 monoketone, (38): 7-amino-3- (2-trifluoromethyl (Phenyl) —2H—isoxolinoline-1 monoketone, (39): 7-amino—3—phenyl—2H-isowahat—1a,

(40) ·· 7-Amino- 3-(2-trifluoromethoxyphenyl) -2H-iso-isoquinone-Dinyl-1 ketone, Φ (41 A): 7- (2-hydroxyethyl (Amine group) —3— (2-trifluoromethylphenyl) —2H—isoquinone—1—1, (41B): 7— [bis (2-hydroxyethyl) amino] —3— (2 1-dichloromethylphenyl)-2H-isoD-quelin-1 1

(4 2 A): 7— (2-Ethylethyl) amino—3—phenyl—2H—isoquinoline—1—one—1—trifluoroacetate, (42B): 7— [bis (2— (Hydroxyethyl) amino] -3-phenyl-2 hydrazone —isoD quinine-1 1 Wish |, • (43 A): 7— (2-hydroxyethylamino) —3— (2-tri (Fluoromethoxyphenyl)-2H-isoDquinoline- 1-one, (43B): 7- [bis (2-hydroxyethyl) amino]-3- (2 -digasoxymethoxyphenyl )-2H-isoD-Querin- 1-wake, (44A) ·· 7- (2-Hydroxyethylamino) -3— (2-trifluoromethoxyphenyl)-2H-isoD-quinoline (11B), (44B): 7— [bis (2-methoxyethyl) amino] —3—phenyl—2Η—isoD quinine—1—one pay, (45): 7- (2 , 3-dihydroxyphenylamino)-3-phenyl- -36- (32) 200536830 2 Η Iso-D-Querin-1 pay, (46): 7- [(2,3-Dihydroxypropyl ()-(2-hydroxyethyl) amino] -3-phenyl-2H-isoquinine-1, (47): 7-[(2-hydroxyethyl) methylamino] -3— (2 Dichloromethylphenyl -2H—iso [ϊQUI 琳 -11 一 酬, (48): 7 — [(2-hydroxyethyl) methylamino] -3—phenyl—2Η—IsoD quelin-1— 酬, Φ (49): 7 — [(2-hydroxyethyl) methylamino] -3— (2-dimethoxymethoxyphenyl) —2Η—isoD-Querin—1— 嗣, (50): 7 — [(2,3-dihydroxypropyl) methylamino] -3—phenyl-2′-isoquinoline-1 monoone, (51): 7— [methyl ((2S, 3R) — 2,3,4-trihydroxybutyl) amino] -3-phenyl-2H-isoquinoline-one-one, (52): (2- {methyl [1-oxo- 3-- 2-trifluoromethoxyphenyl) -1,2-dihydroxyisoDquinoline-7-yl] amino} ethyl H) aminobutyl third butyl ester, (53): 7— [(2 —Aminoethyl) methylamino] —3— (2—trifluoromethoxyphenyl) —2H—isoquinoline—1—one—2—trifluoroacetate (54) ·· 7 — (2 — Aminoethylamino)-3 -phenyl-2H-iso-D-quinoline-1 1-ketone 2 trifluoroacetate, (55): 7- [(2-dimethylaminoethyl) methylamine Base -2H-isoD quinine-1, (56): 7- [(2-aminoethyl) methylamino] -3 -benzene-37- (33) 200536830 Phenolin-1 monoketone 1 trifluoroacetate, (57): 2 -Chloro-N- (1-oxo-3 -phenyl-1,2-dihydroisoquinoline 7-yl) acetamidamine , (58): 2-methoxy-N- (1-oxo-3-phenyl-1, 2-dihydroisoquinoline-7-yl) acetamide, (59): N- ( 1-oxo-3-phenyl-1,2-dihydroisoquinoline-7-yl)-2-phenoxyacetamidamine, • (60): 2-benzyloxy-N — ( 1 monooxo-3-phenyl-1,2-dihydroisoquinoline-7-yl) acetamide, (61): [1 monooxo-3 — (2-trifluoromethylbenzene Group) -1,2-dihydroisoDquinoline-7-yl] urethane, (62): (1 oxo-3-phenyl-1,2-dihydroisoquinoline- 7-yl) urethane, (63): [((1-oxo-3-phenyl-1,2-dihydroisoquinoline-7-ylaminomethylamidino) methyl] amine Tert-butyl carbamate, φ (64): 2 — -N— (1-oxo-3—phenyl-1, 2—dihydroisoDquinoline-7-yl) acetamide 1 trifluoroacetate, (65): 2-morpholine-4 -Yl-N- (1-oxo-3-phenyl-1,2-dihydroisoquinoline-7-yl) acetamide, (66): 2-dimethylamino-N- ( I —oxo — 3 —phenyl — 1, 2- — chloroisoamidine, quinine — 7 —yl] ethylamine, (67): 2-(4-methylpiperazine — 1 —yl) — N- (1-oxo-3-phenyl-1,2-dihydroisoD-quinolin-7-yl) acetamide, (68): 6-morpholin-4-yl-3-yl One 2 Η -isoD_ Linyi-38- (34) (34) 200536830 1 monoketone. A specific example of the present invention includes, for example, the following formula:

And the compounds shown in Table 2. However, the present invention is not limited to these exemplifiers. These compounds can be synthesized in reaction step 2. In addition, the compound names corresponding to the numbers in the table are also described. In the following table, ^ Me ″ indicates a methyl group, and ^ * ″ indicates a bonding site. [Table 2] Compound No. R 1 a R2fi R 3a R4a R5a Y1 Y2 Example 6 9 cf3 HHHHH cir H Example 6 9 7 0 cf3 HHHHH Me) 0 Me Example 7 0 7 1 cf3 HHHHH HO. Example 7 1 7 2 cf3 HHHHH H0 \ 0r Example 7 2 -39- (35) 200536830 7 3 cf3 HHHHH CN- ★ Example 7 3 7 4 cf3 HHHHHQ c) H Example 7 4 7 5 cf3 HHHHH Me〇 / — \ Example 7 5 7 6 * ★ HHHH Example 7 6 7 7 cf3 HHHHH 〇〇- ★ Example 7 7 7 8 cf3 HHHHH Example 7 8 7 9 cf3 HHHHH () H Example 7 9

The compound names corresponding to the above compound numbers are shown below. (69): (4aS, 8Ar) — 3 &gt; — (2-trifluoromethylphenyl) —3, 4, 4a, 5, 6, 7, 8, 8a-octahydro-1H, 2 &quot; Η- [2, 7 /] bisisoquinolinyl-1 / -one, (70): 7-((2S, 6R)-2,6-dimethylmorpholine-4 -yl)-3-(2- Trifluoromethylphenyl)-2H-isoquinoline-1 monoketone (71) ·· 7 — ((S) — 2 -hydroxymethylpyrrolidine-1 -yl) —3— (2 —trifluoromethyl Phenyl)-2H-isoxazolin- 1-one, (72): 7-((R) — 2 -hydroxymethylpyrrolidine-1 1-yl) —3— (2-trifluoromethylphenyl )-2H-isoD-quinoline- 1-ketone, (73) ·· 7-azetidin-1-yl-3- (2-trifluoromethylphenyl)-2H-isoD-quinoline-1 —Ketone, (74): 4a —hydroxyl 3 — — (2-trifluoromethylphenyl) — 3 -40 — 200536830 (36), 4, 4a, 5, 6, 7, 8, 8a — octagas -1H, 2 -H— [2, Ί 〆] bisisoquinolinyl-1 * &quot; monoketone, (75) ·· 1- [1 monooxo-3- (2-trifluoromethylbenzene) Radical) one 1,2—monochloroiso Lin-7-yl] Nanthine-Dingyi-Dianji acid methyl ester, (76): 7- (4-hydroxypiperidine-1-yl) -3- (L) — 1-yl-2 hydrazone —isoD Kuilin 1 1 (, (77): 7 — (1,4 —dioxa 8-azaspiro [4.5] decane

—8 —yl) — 3 — (2-dimethylolphenyl) — 2Η —Isoquinine-1-one, (78): 7— (2-hydroxymethylmorpholine-4 —yl) — 3- (2-dimethylmethylphenyl) -2-iso-D-quinoline-1, 1-ketone |, (79): 7- (4-hydroxy-4, 4-hydroxymethylpiperidine-1, 1-yl)-3 — (2-Dichloromethylphenyl) — 2Η —Isoquinine — 1 monoketone [. A specific example of the present invention includes, for example, the following formula:

And the compounds shown in Table 3. However, the present invention is not limited to these exemplifiers. These compounds can be synthesized in reaction step 1. In addition, the compound names corresponding to the numbers in the table are also described. In the following table, ^ Me "indicates a methyl group," Et "indicates an ethyl group, and" * "indicates a bonding site. -41-200536830 (37) [Table 3] Compound No. R 1 3 R2a R3 a R4a R5 a Y1 Y2 Example 8 0 Η H OMe HHH / ~ \ 0 N- * \ / Example 8 0 8 1 OMe HHHHH / ~ \ 0 N- * \ _ / Example 8 1 8 2 Et HHHHH f ~ \ 0 N- * \ / Example 8 2 8 3 SMe HHHHH / ~ \ 0 N— * \ _y Example 8 3 8 4 Br HHHHH / \ w * Example 8 4 8 5 〇- * HHHHH / \ 〇N— * \ / Example 8 5 8 6 / ~ \ HHHHH / ~ \ 0 N- * \ / Example 8 6 8 7 Cl HHH Me H / &quot; \ 0 N- * \ _ / 8 8 H OMe H OMe HH / ~ \ 0v_ / N-* Example 8 8 8 9 H OMe OMe OMe HH / ~ \ 0 N— * \ _ / Implementation Example 8 9

The compound names corresponding to the above compound numbers are shown below. (80) 3- (4-methoxyphenyl) -7-morpholin-4-yl-2H-isoquinolin-1 monoone, (81): 3- (2-methoxyphenyl) ) —7 —Moryl — 4 —yl — 2H-isoDquinolin — 1 —one, (82): 3 — (2 monoethylbenzyl) — 7 —Moryl — 4 —yl — 2 D. Quilin-1, (83): 3- (2-methylsulfonamidophenyl) -7-morpholine-4, 4-yl-2, -isoD-Quulin-1, 嗣, (84): 3- (2-molyl) -7-morpholin-1 4-radical-2 2 fluorene-42-200536830 (38) iso-isoquinoline-1 monoone, (85): 7-morpholin-4 4-yl —3-(2 Π 一一 一一 一 phenylphenyl) － 2 Η —Iso-D quelin—1 one pay, (86): 7 —Maolin—4—One base—3 — (2 —Ma 卩Lin-4 monoylphenyl) -2 isocyano-1-one, (87): 3- (2-chloro-6-methylphenyl) -7-morpholine 4 4-yl-2 isopropyl Zanthroline 1-one,

(88): 3- (3,5-dimethoxyphenyl) -7-morpholine-4-yl-2 hydrazone-isoquinoline-1-one, (89): 7-morphine-4-- The radical 3- (3,4,5-dimethoxyphenyl)-2 hydrazone-isoD-Querin-1 is paid. A specific example of the present invention includes, for example, the following formula:

And the compounds shown in Table 4. However, the present invention is not limited to these exemplifiers. These compounds can be synthesized in reaction steps 1-7. In addition, the compound names corresponding to the numbers in the table are also described. In the following table, ^ Me "indicates a methyl group" and "*" indicates a bonding site. -43- 200536830 (39)

〔Table 4〕

-44- 200536830 (40)

9 9 Et HHHH ςτ OH-Example 9 9 10 0 ★ 1 \ 1 HHHH ★ OH-Example 10 0 10 1 * ό N o person 0 HHHH τ OH-Example 10 1 10 2 ★ Price η HHHH τ OH- Example 1 0 2 10 3 ★ ΐ HHHH τ OH-Example 10 3 10 4 cf3 HHHH * Φ-Example 10 4 10 5 cf3 HHHH ★ 0 II 0-Example 10 5 10 6 cf3 HHHH-Example 10 6 10 7 cf3 HHHHH. 0,-Example 10 7 10 8 Me H H H H cr-Example 10 8 -45- (41) 200536830

10 9----cr ★ Example 10 9 110 V 1 HHHH-Example 110 111 cr HHHH 〇σ * Example 111 112 cf3 HHHH 0H H-Example 1 1 2 113 cf3 HHHH 6h h-Example 113 114 cf3 HHHH € T-Example 114 115 cf3 HHHH \ ^ N-Example 115 116 cf3 HHHH l / V nn-Example 116 117 cf3 HHHHH 〆-Example 117 118 cf3 HHHH \ 〇b-Example 118 119 cf3 HHHH \ 〆 ★ UH Example 119 12 0 cf3 HHHH HN o Human 0 s-Example 12 0-46- 200536830 (42)

12 1 cf3 HHHH HN o person 0 person-Example 12 1 12 2 cf3 HHHH 0 ^ 0 V-Example 12 2 12 12 3 cf3 HHHH HN ^ o person 0 I-Example 12 3 12 4 cf3 HHHH 〆 * HN o people. -Example 12 4 12 5 cf3 HHHH HN〆 * o human 0 s-Example 12 5 12 6 cf3 HHHH HN〆o human 0-Example 1 2 6 12 7 cf3 HHHH HN〆 * o human 0-Example 12 7 12 8 cf3 HHHH 〆 * HN 〇 person. -Example 12 8 -47- 200536830 (43)

12 9 cf3 HHHH HN o human 0 s 0,-Example 12 9 13 0 cf3 HHHH HN〆 * o human 0 Vx)-Example 13 0 13 1 cf3 HHHH HN〆 * o human 0 s OH Example 13 1 13 2 cf3 HHHH 9 O 0 person fsT * έό-Example 13 2 13 3 cf3 HHHH ό H-Example 13 3 13 4 cf3 HHHH HN 0 * ^ 0-Example 13 4 13 5 cf3 HHHH HN〆 * ό- Example 13 5-48- (44) 200536830

13 6 cf3 HHHH HN o Human 0-Example 13 6 13 7 cf3 HHHH HN S ^ O k-Example 13 7 13 8 cf3 HHHH OH 〇 Human f OH H — Example 13 8 13 9 cf3 HHHH ηοί 0 h〇 ^ a0An. * H-Example 13 9 14 0 a * HHHH HN〆 * 0 ^ 0-Example 14 0 14 1 cf3 HFHH HN 0 ^ 0-Example 14 1 14 2 〇cf3 HHHH HN cr ^ o Implementation Example 14 2 14 3 cf3 HHHHY c ^ o-Example 14 3 14 4 cf3 HHHHY o Human 0 k ^ 〇H-Example 14 4 14 5 Me H OH HH g * OH-Example 14 5 14 6 Cl HHHH cr -Example 14 6 -49- (45) 200536830

14 7 Η HHHH HN Λ OH-Example 14 7 14 8 Η HHHH OH OH OH H-Example 14 8 14 9 cf3 HHHH 1, N〆 * H-Example 14 9 15 0 cf3 HHHH 1, N〆 * 1-Example 15 0 15 1 cf3 HHHH-Example 15 1 15 2 cf3 HHHH-Example 15 2 15 15 cf3 HHHHOV * 1-Example 15 3 15 4 CF3 HHHH-Example 15 4 15 5 cf3 HHHHH- Example 15 5 15 6 HHHHHX-Example 15 6 16 2-----Λ) Example 16 2 16 3-----Or * Example 16 3 16 4 CF3 HHHHO 1 i H-Example 8 7 -50- 200536830 (46) The compound names corresponding to the above compound numbers are shown below. (90): 7- (3-hydroxypiperidine- 1-yl) -3- (4-methoxy-2-methylphenyl)-2H-isoDquinoline- 1-one, (91): 7— (3-Jing Ji calls H 1—1 1 radical) —3— (2 —Merlin—4 1-phenylphenyl) —2 Η—Iso-D-Querin—1—Reward, (92): 7 — ( 3 — 1-based via base pulse D) — 3 — 0 —tolyl — 2 Η — isoD Quirin — 1 wake up,

(93): 7- (3-hydroxypiperidine-l-yl) -3- (6-methoxybenzothiazole-2-yl) -2'-isoDquinoline-l-one, (94): 7 — (3-hydroxypiperidine-1 1-yl) — 3 — (2 —Moryl-4 —Methylphenyl) — 2 — —Isoquinine-1 1 —, (95): 7 — ( 4-Hydroxypiperidin-1-yl) -3- [2- (methylphenylamino) phenyl]-2Η-isoD-Querin-1-amyl, (96): 3- (4-fluoro- 2-trifluoromethylphenyl)-7- (4-determined by radicals B 1-1)-2 Η-isoD quinine-1 pay, (97): 7-(4-hydroxypiperidine- 1-based) —3— (2 —Moryl-4—ylphenyl) —2 hydrazone—Isoquinone—Din—1—Pay, (98): 3—Biphenyl—2—Base—7— ( 3-Hydroxypiperidine-l-yl) -2 hydrazone-isoD-Querin-I-1, (99): 3- (2-ethylphenyl) -7- (3-hydroxypiperidine- 1-yl ) —2Η-IsoΠ1—1—Wake up, (100): 7— (4-Hydroxypiperidine- 1-yl) —3- [2- (2-methoxyethoxy) phenyl] — 2Η-isoΠquinoline-1 monoone, (101 ): 4- {2— [7— (3-hydroxypiperidine-1-yl) — -51-200536830 (47) 1 monooxo-1,2-dihydroisoquinoline 3-yl] benzene Methyl} piperazine-1 monocarboxylic acid tert-butyl ester, (10 2): 7 1 (3- —Diphenyl group 1 —yl) — 3 — (2-pyrazine 1-ylphenyl) — 2H-isoquinoline-1-one, (103): 7- (3-hydroxypiperidine-1-yl) -3- [2- (4-methylmethylpyridin-1-yl) phenyl] -2H —IsoD-Querin—1— (10 4): 7 —thiomorpholine— 4—yl—3 — (2 —trifluoromethyl

(Phenyl)-2 Η —Iso-D-Querin-1 — 1, (105): 7 — (1 —Oxothiothiomorpholine — 4-yl) — 3 — (2-Dichloromethylphenyl) 1 2Η-isoquinolin-1 1-ketone, (106): 7- ((R) 3 -hydroxypiperidine-1-yl) -3 3 (2-difluoromethylphenyl) 2 2 -isoD Quinoline-1 monoketone, (107): 7— ((S) — 3-via radical D-1—1-yl) —3- (2-dichloromethylphenyl) —2Η—isoquinolin-1 1 嗣, (10 8) 7 —Moryl — 4 —yl — 3 — 〇 —Tolyl — 2 Η —Isoquinyl — 1 waking up, (10 9): 7 —Moryl — 4 —Myl — 3 — (L) — 2 —yl — 2 fluorene — isoDquinoline — 1 —one, (110): 3 — (2 —dimethylaminophenyl) — 7 —morpholine — 4 —yl — 2 Η —Iso-D Quilin—1 —Reward '(111): 7 —Morlin—4—Base—3— (2-Laluoyuan—1-phenylphenyl) —2 Η—Isolation—1—Reward '(112): 7— ((S) — 2,3 —dihydroxypropylamino) — 3 — (2—dichloromethylphenyl) —2Η—isoD-Querin—1—1, -52 -200536830 (48) (113): 7— ((R) — 2, 3 (Dihydroxypropylamino)-3-(2-dimethylphenyl)-2H-isoquinoline-1 -one, (114): 7 -imidazole-1 -yl-3-(2-trifluoromethyl) Phenyl) -2, hydrazone, iso-D, quinine-1, fluorene, (115): 7- [1,2,4] triazole-1-yl-3- (2-trifluoromethylphenyl)- 2Η-isoquinoline-1 monoketone, (116): 7-tetrazol-1-yl-3- (2-trifluoromethylphenyl

)-2 Η —Iso-D 咐 一 1 (, (117): 7- ((R) — 3-Benzyloxy-2 —methylaminopropylamino — 3-(2-trifluoro (Methylphenyl)-2Η-isoquinoline- 1 -one, (118) ·· 7- ((R)-4 -benzyloxymethyl- 3 -methyl flavor 1: 1 sitting courtyard 1- Group) —3— (2-dichloromethylphenyl) —2Η—Isoquinoline—1 monoketone, (119): 7—methylamino—3— (2-trifluoromethylphenyl) — 2 Η Iso-isoquinine — 1 — 嗣, (120): [1-oxo-3- 3 — (2-trifluoromethylphenyl) — 1,2-dihydroisoquine 1-7-yl ] Propylaminoformate, (121): [1 monooxo-3-(2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] isopropylaminoformate Esters, (122): [1-oxo-3— (2-trifluoromethylphenyl) —1,2-dihydroisoquinoline-7-yl] isobutylcarbamate, (123) : [1 monooxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoDquinoline-7-yl] amyl carbamate, -53- 200536830 (49) ( 124): 〔1—oxo group 3 — (2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] benzylaminoformate, (125): [1-oxo-3-(2-trifluoro (Methylphenyl) —1,2-dihydroisoD-quinolin-7-yl] allyl carbamate, (126): [1 monooxo-3- (2-trifluoromethylphenyl) ) —1,2-dihydroisoD-quinolin-7-yl] butadiene carbamate, (127): [1-oxo-3— (2-trifluoromethylphenyl) —

1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid 2- (2-methoxyethoxy) ethyl ester, (128) ·· [1-oxo-3— (2 -tri Fluoromethylphenyl) —1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid 3-methoxy-2,2-dimethylpropyl ester, (129): [1 monooxo 3- (2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid 2-methoxyethyl, (130): [1-oxo-1 3- (2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid 2-benzyloxyethyl ester (131): [1 monooxo-3 — (2-trifluoromethylphenyl) —1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid 2-hydroxyethyl, (132): [1-oxo-3— (2 —Trifluoromethylphenyl) —1,2-dihydroisoquinoline-7-yl] carbamic acid (R) —2,3-bisphenoxypropyl ester, (133): [1-oxyl 3- (2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid 2-benzyloxy-1 1-54- 200536830 (50) benzene Methoxymethyl Esters, (134): [1-oxo-3-(2-trifluoromethylphenyl)-1, 2-dihydroisoquinoline-7-yl] cyclohexyl methylcarbamate, (135 ): [1-oxo-3- (2-trifluoromethylphenyl) —1,2-dihydroisoquinoline-7-yl] carbamic acid cyclohexane, (136): [1- Oxo-3- (2-dimethylphenyl) -1,2-dihydroisoD-quinolin-7-yl] furan-3-methyl ester,

(137) ·· [1-oxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoD-quinone-7-yl] thioaminocarboxylic acid S-ethyl ester, (138): [1-oxo-3 — (2-dimethylphenyl) — 1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid (R) — 2,3-dihydroxy Propyl ester, (139): [1-oxo-3— (2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] carbamic acid 2-hydroxy-1— Hydroxymethyl ethyl ester, (14 0): [3- (2-morpholine-4-ylphenyl) -1,1-oxo-1,2-dihydroisoline-7-yl] aminocarboxylic acid Ethyl ester, (141): [3- (4-Fluoro-2-trifluoromethylphenyl) -1-oxo-1,2-dihydroisoquinoline-7-yl] urethane , (142) ·· [1-oxo-3- (2-trifluoromethoxyphenyl) -1,2-dihydroisoquinoline-7-yl] carbamate, (143) · Methyl [1-oxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoD-quinolin-7-yl] carbamate, (144): base〔 1-oxo-3- (2-difluoromethylphenyl-55-200536830 (51))-1,2-dihydroisoDquinoline-7-yl] aminocarboxylic acid 2-hydroxyethyl ester ( 14 5): 3- (4-Cyclo-2-methylphenyl) -7- (3-hydroxypiperidine-1-yl)-2H-isoDquinoline-1-one, (14 6) · 3 — (2 —phenyl) — 7 — morphine 1 — 4 — 2 — hydrazone — isoD 1 — ketone,

(147): 2-Cyto-N- (1-oxo-3-phenyl-1,2-dihydroisoD-quinolin-7-yl) acetamide, (148): 3-phenyl —7— ((2S, 3R) — 2,3,4-Dimerylbutylamino) —2H-isoDquinoline—1 monoketone, (149): 7- (2,2 —dimethyl Group) -3-(2-trifluoromethylphenyl) -2 hydrazone -isoD quelin-1-wake up, (150): 3-(2-trifluoromethylphenyl) -7-(1, 2,2-dimethyl group)-2 fluorene-iso-D-Querin-1-fluorene, (151): 7-(N-diphenylmethylene group)-3-(2-difluoromethylphenyl group) ) -2Η-Isoquinoline-1 monoketone, (15 2): 1-methyl-1 3- [1 monooxo-3— (2-dichloromethylphenyl) -1,2- Command a 7-yl] urea, (15 3) · Ν-methyl-N — [1-oxo-3 — (2-difluoromethylphenyl) -1,2-dihydroisoquinone Phenyl-7-yl] formamidine, (154): N- [1-oxo-3-(2-trifluoromethylphenyl) -1,2-dihydroisoD-quinolin-7-yl ] Benzamidine, (155): Ν— 〔1 monooxo-3 (2-Difluoromethylphenyl) -1,2-dihydroisoD-quinolin-7-yl] -2-thiophene-2-ylacetamidine-56-200536830 (52) Amine, (156) ·· N— [1-oxo-3-phenyl-1,2-dihydroisoD-quinolin-7-yl] acetamide, (162): 3-furan-2-yl-7-morpholine-1 4-methyl-2}]-isoquinoline-1 monoketone, (16 3) 'Ί monomorphine 4- 4-yl-3 卩 Π Π Π 一 一 一 一 一 吗 D dilinole 1-one ketone 2 three Fluoroacetate,

(164): 2-Hydroxy-3-3- [1-oxo-3-3- (2-trifluoromethylphenyl) -1,2-dihydroisoD-quinolin-7-ylamino] propanoic acid methyl ester The specific examples of the present invention include, for example, the following formulas:

And the compounds shown in Table 5. However, the present invention is not limited to these exemplifiers. [Table 5] Compound No. R1 R2 Example 1 57 C1 Η Example 157 1 58 Η Cl Example 1 5 8 159 Cl Cl Example 159 160 F 实施 Example 160 16 1 Η F Example 1 6 1 -57- (53) 200536830 The following are the compound names corresponding to the above compound numbers. (157) ·· 6—Gas-7—Do you want a 4-Aiyl-3— (2-Dimethylmethyl) -2H-isoDquinoline-1 monoketone, (158): 8—Chloro-1 7 —morpholine—4—yl—3— (2-trifluoromethylphenyl) —2H—iso [Iquinoline—1-one,

(159): 6,8-dichloro-7-morpholine-4-yl-3-(2-trifluoromethylphenyl) -2H-isoDquinoline-1 monoone, (160): 6- Fluorine | —7—Moryl—4—Methyl—3— (2—Dimethyl methyl radical) —2 卩 —Isoamidine—1—Remuneration, (161): 8—Fluoro 7—Morpholine—4— A 3- (2-trifluoromethylphenyl)-2H-isoquinoline- 1-one, and a method for producing the compound of the present invention will be described next. In addition, in the production method shown below, when an unexpected chemical conversion is performed under the conditions based on the implementation method as defined, the production method can be implemented by, for example, functional group protection or deprotection. Among them, the selection and removal of protective groups can be exemplified by imitating (I "Greene and Wu t s, Protective Group in Organic

Sythesis ^ (2nd edition, John Wiley &amp; Sons 1991) "These can be used in accordance with the reaction conditions. If necessary, the order of reaction steps such as introduction of a substituent may be changed. As a method for producing the compound of the present invention represented by the general formula (!), Various methods can be used. Although it can be synthesized by general organic synthesis means, the following methods are exemplified as representative production methods. -58- (54) (54) 200536830 Representative production method The compound represented by the formula (1) of the present invention can be produced, for example, by the following method. However, the production method of the compound of the present invention is not limited to these. The compounds of the present invention are all novel compounds not described in the literature, but can be produced by known methods. In addition, the raw material compound used in the production can be a commercially available one 'or can be produced by a conventional method if necessary. In the following reaction steps 1 to 4 and the description thereof, X and γ represent Y1, Y2, γ], Υ1, Υ1, and Υ3 are synonymous with those described in the formula (1). In addition, the abbreviations used in the following reaction formulas are general thoughts understood by those skilled in the art. Further, "L represents a chlorine atom or a bromine atom, and g represents a Ci-4 ^ 7C group such as a hydrogen atom or a methyl group." T represents a C] -6 group. 1. General synthesis method of compound (1a) of formula (1) (γ1 and Y3 represent hydrogen atoms) Reaction Step 1

-59-1 1-methylbenzylamine derivative II can be easily produced from a known 2-methylbenzoic acid 2 benzoic acid derivative I using one side of the amidation method. The compound represented by Formula 111 is obtained by separating and purifying the obtained 2-methylbenzylamine derivative π by a known method (aromatic amination reaction: Wolfe, JP9 J. Org. Chem.? 65? 1158-1174 (2000), Harris, MC, 3

Org. Lett ·, 4, 2 8 8 5-2 8 8 8 (2 002), Huaug5 X.5 Org. Lett., 200536830 (55) 3, 3417-34 1 9 (200 1)). That is, the compound represented by the formula m is 2-methylbenzylamine derivative 11 in a suitable solvent (toluene, butane HF, 1,4-dioxane, xylene, dimethoxyethane, etc.), Appropriate palladium catalyst (for example, Pd (〇Ac) 2, Pd2dba3,

PdCl2 CP (ο-tol) 3] 2, Pd (02CCF3) 2 etc.), ligands (for example, P (o— tol) 3, BINAP, DPPF, P (t — Bu) 3, 2 dicyclohexyl Phosphino-2 / — (N, N-dimethylamino) biphenyl, 2 mono (di-tertiary butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl 2,6 &gt; — Dimethoxy-2— (dicyclohexylphosphino) biphenyl, 2,1,4 /, — —triisopropyl — 2- (dicyclohexylphosphino) biphenyl — * Odor, iron salt, etc.), and experience (t—BuONa, LiHMDS, Cs2C03, K3OP4, etc.), and the amines prepared with commercial reagents or known methods at an appropriate temperature (room temperature to the boiling point of the solvent) Prepared by reaction. From the obtained compound represented by Formula 111, a known method is used (U.S. Patent No. 4,942,63; Won-jea Cho, et al., Arch. Pharm. Res., 20, 264-268 (1 997); Bioorg.

Med. Chem. Lett · 8, 4 1 — 46 (1 998); Arch. Pharm. Res.? 24, 27 6-280 (200 1); Bioorg. Med. Chem. 1 0, 29 5 3 -2961 ( 2 002)) to produce a compound of formula (la). That is, the compound represented by Formula (la) is a compound represented by Formula 111 with an appropriate solvent (for example, THF and Et20) and an appropriate base (for example, LDA, t-BuLi, s-BuLi, and Bi ] L i) Lithification at an appropriate temperature (for example, 7.8 ° C to the boiling point of the solvent), and at a suitable temperature (for example, -7 ° C to the boiling point of the solvent), the aroma is prepared with a commercial reagent or a known method. Group or heteroaromatic nitrile derivative-60-200536830 (56) prepared by the reaction of organisms. 2. General synthesis method of compound (ib) of formula (1) (Y) and Y4 represent a hydrogen atom) Reaction Step 2

The 2-methylbenzamide derivative II obtained in the reaction step 1 was subjected to the same well-known method as in the reaction step I (U.S. Patent No. 4,942,163; Won-Jea Cho, et al.? Arch. Pharm. Res., 20? 264-26 8 (1 997); Bioorg. Med. Chem. Lett. 8, 4 1 -46 (1 998); Arch. Pharm. Res., 24, 2 76-2 80 (200 1 ); Bioorg. Med.

Chem. 10, 29 5 3 -296 1 (2002)) to obtain a compound represented by formula (IV). The compound represented by the formula (1 b) is a known method (aromatic amination reaction: W ο 1 fe, J. P., J. Ο rg. Chem., 65, 1 1) which is the same as that used in the reaction step i. 5 8- 1 1 74 (20 00); Harris, MC? Org. Lett., 4, 28 8 5- 2888 (2002); Huaug, X ·, Org. Lett ·, 3, 34 17-3419 (2001) ) To produce a compound represented by formula (IV). 3. General synthesis method of compound (1 d) of formula (1) (γ1 and γ4 represent hydrogen atoms) -61-200536830 (57) Reaction step 3

(1d) Use of the compound represented by formula (IV) and the reverse method (aromatic amination reaction: Wolfe, J. p 1 1 5 8-1 1 74 (2000); Harris, MC? 2888 (2002); Huaug , X.? Org. Lett.)). The obtained formula (1c) is compared with a method (for example, a reductive amination reaction) to produce a compound.

4. · General hydrogen atom of compound (1 e) of formula (1)) Reaction step 4 X Amidation reaction Step 2 is the same as that used in Step 2. J. Org. Chem ”65, Org. Lett ? 4, 2 8 8 5-, 3, 3417-3419 (The compound shown in 2001 uses a well-known formula (1 d)) (Y1 and Y 4 represent

0

(1e) (10) The compound represented by the formula (1e) is a compound represented by the formula (1c) in which a compound represented by the general formula (1c) is appropriately dissolved: Dioxane and xylene dimethoxyethyl are prepared by the amidation reaction used in step 3. Immediate agents (toluene, tetrahydrofuran, diethyl ether, dichloromethane-62- 200536830 (58) alkanes, pyridine, N, N-dimethylformamide, dimethylasyl, etc.), appropriate test groups (such as Diethylamine, fluorene ratio 11 疋, etc.), and the reaction with the appropriate temperature (-78 ° C to the boiling point of the solvent) in the presence of acid anhydride or acid halide. 5 · General synthesis method of compound (1 f) of formula (1) (γ) and γ4 represents a hydrogen atom)

The compound represented by the formula (V) is a compound represented by the formula (! V) by a known method (aramid amination: Fukuyama, T., Org. Lett) 5, 49 8 7-4990 (2003) Synthesized. That is, the compound represented by the formula (V) is a compound represented by the formula (I v) in a suitable solvent (N, N _ monomethylformamide, monomethyl asus, etc.), a suitable copper catalyst (metal Ketone (powder), copper chloride (I), copper oxide (I), copper oxide (11), copper chloride (π), copper sulfate (11), copper sulfate (11), acetic acid, copper acetate (Π), Copper iodide (I), copper triflate (1), etc.) and alkali (acetic acid planer, potassium phosphate, potassium carbonate, carbonic acid planer, sodium tert-butoxide, potassium hexamethyldisilazane, six In the presence of sodium methyldisilazane, phosphine, etc.), it is prepared by reacting a commercially available reagent or an appropriate amine compound prepared by a known method at an appropriate temperature (room temperature to the boiling point of the solvent). The compound represented by the formula (i f) is obtained from the obtained compound represented by the formula (v) in the same manner as in Steps 3 to 4 of the reaction. -63- 200536830 (59) 6 · General synthesis method of compound (1 g) of formula (1) (γ1 and γ4 represent hydrogen atoms)

The compound represented by the formula (ν I) is a compound represented by the formula (1 c) used in the reaction step 3, which can be easily produced by a halogenation reaction such as a Sandmie reaction. The compound represented by formula (1 g) is a compound represented by formula (VI) by a known method (copper catalyst heteroarylation reaction: Buchwald, S, L ·, J. Am. Chem. Soc. 5 123 , 7727-7729 (2001), Buchwald, SL? J. Am. Chem. Soc., 124, 7421-74: 28 (2 002)). That is, the compound represented by formula (lg) is a compound represented by formula (IV) in an appropriate solvent (dioxane, tetrahydrofuran, diethyl ether, toluene, etc.), an appropriate copper catalyst (metal ketone (powder), chlorination). Copper (I), copper oxide (I), copper oxide (II), copper (II) chloride, copper sulfate (Π), copper (II) sulfate, copper acetate (II), ethyl acetate, copper iodide (I), Copper (I) trifluoromethanesulfonate, etc.), ligands (eg 1,2-cyclohexanediamine, N, N # —dimethylethylene diamine, N, N, dimethyl-1) , 2-cyclohexanediamine, 1,10-phenanthroline, etc.) and bases (potassium phosphate, potassium carbonate, carbonate carbonate, sodium tert-butoxide, potassium hexamethyldisilazane, hexamethyldisilazide In the presence of sodium alkoxide, phosphonium phosphonium, etc.), it is prepared by reacting with an appropriate heteroaromatic compound or amidine compound prepared by a commercially available reagent or prepared by a known method at an appropriate temperature (room temperature to the boiling point of the solvent). -64- 200536830 (60) 7. General Synthesis of Compound (丨 ") of Formula (1) (γ1 and γ4 represent independent hydrogen or halogen atoms) Reaction Step 7

(1j)

The compound represented by the formula (v II) is obtained by subjecting the 2-methylbenzylamine derivative π I obtained in the reaction step 1 to a known method (halogenation: J. Org · Chem "6 3 (10), 33 7 9 -33 8 5 (1 998), Heterocycles, 29 (4), 649-65 1 (1 989)). That is, represented by formula (VII)

The compound shown is that 2-methylbenzylamine derivative III in an appropriate solvent (acetonitrile, methylene chloride, etc.) and a halogenated reagent (N, N / -difluoro-2 '2 / -bispyridine Bis (tetrafluoroborate), N-chlorinated succinyl imine, etc.) are prepared by reacting at an appropriate temperature (-7 to 8 t to the boiling point of the solvent). The compound represented by formula (lj) is a compound represented by formula (VII-65- (61) (61) 200536830) obtained by a known method in reaction step 1 (US Pat. No. 4,942,63); Won- Jea Cho, et al., Arch. Pharm. Res "20, 264-268 (1997); Bioorg. Med. Chem. Lett. 8, 4 1 -46 (19 9 8); Arch. Pharm. Res ·, 24, 276-280 (2001); Bioorg · Med. Chem. 10, 295 3 -296 1 (2002)) and the formula (1 h) or formula (1) synthesized by reaction steps 1 to 4 j) The compound represented by known method (halogenation: J. Or g. Chem., 63 (1 0), 337 9-3385 (1 9 9 8), Heterocycles, 29 (4)? 649-65 1 (1 9 8 9)). Synthesis of raw material compounds. Part of the raw material compounds of the compounds of the present invention are new compounds. These compounds are the same as the known raw material compounds and can be easily synthesized by methods known to the industry. The above is the formula for the present invention. (1) Example of a method for producing a compound 'The isolation and purification of the target compound shown in the above reaction steps can be applied to extraction, concentration, distillation, and crystallization. , Filtration, recrystallization, various chromatography, and other general chemical operations. The compounds of the present invention and their pharmaceutically acceptable salts contain all stereoisomers of the compound represented by formula (1) (for example, Contains symmetrical isomers, asymmetric isomers (cis or trans geometric isomers)), racemates of the aforementioned isomers, and other mixtures. Also, the compound of the present invention and its pharmacologically acceptable The salts include several tautomeric forms, such as enol and imine forms, keto and enamine-66-200536830 (62) forms, and these mixtures. Tautomers can be used in solution to Tautomeric mixtures exist. The solid form is generally dominated by one tautomer. Although only one tautomer is described, the present invention includes all tautomers of the compounds of the present invention. When the compound of the present invention is obtained as a free body, the compound can be converted into a salt or a hydrate or a solvent state that the compound can form according to a conventional method. # Further, the compound of the present invention When the compound is obtained in the form of a salt, a hydrate, or a solvent, it can be converted into a free form of the compound according to a conventional method. The compound of the present invention or a pharmaceutically acceptable salt thereof has excellent antitumor properties. Effect, and the stability in the body and solubility in water are also excellent, suitable for preventive or therapeutic agents for cell proliferative diseases (especially therapeutic agents). The compound of the present invention or a pharmaceutically acceptable salt thereof is applicable to breast cancer, colorectal cancer, ovarian cancer, lung cancer, pancreas # cancer, liver cancer, uterine cancer, brain cancer, prostate cancer, and acute leukemia. It is used as a preventive or therapeutic agent (especially a therapeutic agent) for cell proliferative diseases of various cancers such as gastric cancer. These methods include the step of administering a pharmaceutically effective amount of a pharmaceutical composition containing the disclosed compound of the present invention or a pharmaceutically acceptable salt thereof to a patient having a disease or condition that must be treated. When the medicinal composition of the present invention is used as a therapeutic or preventive agent for cell proliferative diseases such as cancer, the administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), and intracavitary Intracavity, Intraperitoneal cavity -67- 200536830 (63) 'Local (drop, powder, ointment, glue or cream) administration and inhalation (intracavity or nasal spray), etc. Examples of the dosage form include lozenges, capsules, granules, powders, nine-dose, aqueous and non-aqueous oral solutions and suspensions, and divided into the respective dosages and filled in appropriate containers. Non-oral solution. In addition, the administration form also includes various administration methods such as a subcutaneous transplantation to regulate the release of a prescription. The above formulations can be prepared by known methods using additives such as excipients, lubricants (coating agents), binders, disintegrating agents, stabilizers, flavoring and deodorizing agents, and diluents. Examples of the excipients include starches such as starch, potato starch, and corn starch, lactose, crystalline cellulose, and calcium hydrogen phosphate. Examples of the coating agent include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ceramics, talc, carnauba wax, and paraffin. Examples of the binding agent include polyvinylpyrrolidone, MaCrOgol, and the same compounds as the aforementioned excipients. Examples of the disintegrator include the same compounds as the aforementioned excipients, and chemically modified starches and celluloses of cross-linked methyl cellulose sodium, carboxymethyl starch sodium, and cross-linked polyethylene tj-pyrrolidone. class. Examples of stabilizers include parabens of methyl preservatives and propyl preservatives; alcohols of chlorobutanol, benzyl alcohol, and benzyl alcohol; ammonium chlorobenzyl chloride; phenol and cresol Phenols; Ethylmercury sodium thiosalicylate; dechloroacetic acid; and sorbic acid. As the flavor correcting agent, for example, sweeteners, sour flavors, -68-200536830 (64) flavors and the like can be generally used. Further, as a solvent for producing a liquid agent, ethanol, phenol, chlorocresol, pure water, distilled water, and the like can be used. Examples of the surfactant or emulsifier include polysorbate 80, stearic acid polyoxy 40, and lauryl macrogol.

When the pharmaceutical composition of the present invention is used as a therapeutic or preventive agent for a cell proliferative disease, the amount of the compound of the present invention or a pharmaceutically acceptable salt thereof depends on the symptoms, age, race, relative health status, Other dosing and administration methods vary. For example, for patients (constant temperature animals, especially humans), the general effective amount is as an active ingredient (the compound of the present invention represented by formula (1)) in the case of an oral preparation, and the daily dosage per 1 kg of body weight is 0.01 to 1000 mg, preferably 0.1 to 300 mg per 1 kg of body weight, and the daily dosage is preferably in the range of 1 to 5 000 mg for an adult patient of general weight. In the case of a parenteral preparation, the daily usage amount per lb of body weight is from 0.01 to 10,000 mg, preferably from 1 to 5,000 mg per 1 kg of body weight. Administration based on symptoms is preferred. The present invention provides a 1- (2H) -isoquinoline derivative having excellent antitumor effect. The present invention also provides a compound useful for a cell proliferative disease such as an effective therapeutic and preventive agent for cancer, a method for producing the same, an intermediate compound useful in the method, and a pharmaceutical composition containing these compounds. [Embodiments] Examples -69- 200536830 (65) The present invention will be described in more detail by examples below, but the present invention is not limited to these examples. In addition, N M R is analyzed as JNM-Εχ 2 70 (270 MHz), JNMGSX400 (400MHz), or JNM — A500 (500MHz) manufactured by J Ε Ο. The NMR data is expressed in ppm (parts per

million), referring to the deuterium signal from the sample solvent. The mass spectral data is JMS-DX303 or JMS-SX / SX102A manufactured by JEOL, and the mass spectral data possessed by high-speed liquid chromatography is the micromass attached to 99 6-6 0 0E gradient high-speed liquid chromatography manufactured by Waters. (ZMD manufactured by micromass) or micromass (ZQ manufactured by micromass) attached to 2525 gradient high-speed liquid chromatography manufactured by Waters. The high-speed liquid chromatography conditions are as follows. High-speed liquid chromatography conditions 1 column: Combi ODS (ODS, 5 // m, 4.6 mm I · D. Χ 50 mm, manufactured by Wako Pure Chemical Industries, Ltd.), COSMOSIL (ODS, 5 // m, 4.6 mm ID χ 50 mm, manufactured by Nacalai Tesque), or Inertsi 1 C 1 8 (ODS, 5 // m, 4 · 6 mm I · D · χ 50 mm manufactured by GLscience) Mobile phase: 0.05% Water (A) of fluoroacetic acid and acetonitrile (B) containing 0.05% trifluoroacetic acid: from 10% B to 95% B (3.5 minutes), from 95% B to 10% B (1 minute ), Stepwise solvent gradient dissolution at 10% hold (0.5 minutes). Flow rate: 4.0 m L / min -70-

200536830 (66) High speed liquid chromatography condition 2 column: Combi ODS (〇DS, 5 &quot; m, 4.6 50mm, manufactured by Wako Pure Chemical Industries, Ltd.), COSMOSIL (// m '4.6 mm IDx50 mm &gt; Nacalai tesque ^

I nertsi 1 C 1 8 (0 DS '5 // m, 4 · 6 mm I · D manufactured by GLscience) Mobile phase: water containing 0.05% trifluoroacetic acid (A)% trifluoroacetic acid in acetonitrile (B) dissolution Method · Stepwise solvent gradient from 30% B to 35% B (0.2 minutes) to 98% B (3.3 minutes), from 98% B to 30% B maintained at 30% (0.5 minutes) Dissolution flow rate: 4.0 mL / min. High-speed liquid chromatography conditions. 3 Column: Combi ODS (ODS, 5 // m, 4 · 6 η mm, manufactured by Wako Pure Chemical Industries, Ltd.), mobile phase: water containing acetic acid (A ) And acetonitrile dissolution method containing 0.05% trifluoroacetic acid: from 10% B to 95% B (2 minutes), (1.5 minutes), from 95% B to 10% B (1 minute) held (0.5 minutes ) Stepwise solvent gradient dissolution. Flow rate: 4.0 mL / min. The organic synthesis reaction is the purchased reagent without further purification. 1 It is in the range of 20 ~ 25 t. All water-repellent reactions mm I. D χ: ODS, 5 &gt; Division), or χ 50 mm, and containing 0.05, 35% B (1 minute), separated. m I. D. χ 50 0.005% Trifluoro (B) was maintained at 95% and performed at 10%. Room temperature under nitrogen environment -71-200536830 (67). Concentration or solvent distillation under reduced pressure is carried out in a rotary still unless otherwise mentioned. For the preparation of the compound, if necessary, the functional group may be protected by a protecting group, and the protecting group of the target molecule is prepared, and then the protecting group is removed. The selection of the protecting group and the debasing operation can be performed using, for example, the methods described in "Greene and Wilts", "Protective Group in Organic Synthesis", 2nd Edition, John Wiley &amp; Sons 1991.

[Example 1]

7-Chloro-3- (2-Dimethylmethylphenyl)-2H-isoD-quinoline-1 monoketone Step A 5 -Chloro-2, N -dimethylbenzidine

CI

Add 25.0 g (147 mmol) of 5-chloro-2-methylbenzoic acid to 4 2 · 8 m L (5 8 6 mm ο 1) thionyl chloride and stir under heating and reflux for 1.5 hours. The excess thionyl chloride was removed by distillation. The remaining residue was dissolved in 140 mL of dichloromethane, and 34.2 mL (440 m m ο 1) of 40% methylamine was dropped into the ice bath, followed by stirring at 0 ° C overnight. The reaction solution was extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 ~ 3: 2) to obtain 24.2 g (90%) of 5-chloro-2, N-dimethylbenzene as a colorless solid. Formamidine. ··· 2 · 40 (3H, s) H-NMR (270MHz, CDC13) (5 (ppm) -72-200536830 (68)), 2.99 (3H, d, J = 4.6 Η z), 5.77 (1H, brs), 7.15 (1H, d, J-8.3Hz), 7.27 (1H, dd, J = 2.3, 8.3Hz), 7.33 (lH, d, J = 2. · 3Ηζ) ESI (LC-MS positive Type) m / zl84 (M + H).

Step B 7-Chloro-3- (2-trifluoromethylphenyl)-2H-isoquinoline-1 monoketone

45.3 mL (81.6 mmol) of a 1.8M solution of lithium diisopropylamidine in THF was diluted with 68 mL of THF, and then at a temperature of 78 ° C, 28 mL of 5.8 g (27.2 mmol) prepared in Step A was added dropwise. 5-Chloro-2, N-dimethylbenzamide solution in THF. Here, 28 mL of a 4.65 g (27.2 mmol) solution of 2-trifluoromethylbenzonitrile in THF was added, and the mixture was stirred at 78 ° C for 2.5 hours. After the reaction solution was warmed to room temperature, a saturated ammonium chloride aqueous solution was added, and then extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous sodium sulfate. The resulting solid was concentrated under reduced pressure and filtered to obtain 6.87 g (78%) of 7-chloro-3- (2-trifluoromethylbenzene) as a colorless solid. Base) —2H—Iso-D-Querin—1—H-NMR (2 70MHz ^ CDC13) 5 (ppm): 6_49 (1H, s), 7.37—7.72 (5H, m), 7.81— 7.84 (lH, d, J =

7.26Hz), 8.32—8.33 (lH, d, J = 1.65Ηζ), 9.18 (1H, brs) E SI (LC — M S positive type) m / z 3 2 4 (M + H). -73- 200536830 (69) The compounds shown below (Example 2, Example 3) were synthesized by a method similar to Step B of Example 1. [Example 2] 7-Chloro-3-phenyl-2H-isoD-quinine fl 1- 1

〇

CI

iH-NMR (2 70MHz, CDC13) δ (ppm): 6.74 (1 (, s), 7.26-7.56 (4H, m), 7.61-7.66 (3H, m), 8.28 (lH, d , J = 2.3Hz), 9.02 (lH, brs) ESI (LC-MS positive type) m / z256 (M + H). [Example 3] 7-Chloro-3-(2-trifluoromethoxyphenyl)-2H-iso-D-quinoline-1-

W-NMR (270 MHz, DMSO-d6) 5 (ppm): 6.72 (1H, s), 7.51-7.56 (2H, m), 7.59-7.70 (2H, m), 7.78 (lH, s), 7.79 (lH, s), 8.15 (lH, s), 11.81 (1H, s) ESI (LC-MS positive) m / z340 (M + H). -74- 200536830 (70) 〔Example 4〕 7 — Korbiline — 1-based — 3 — (2-trifluoromethylbenzene, quinolinone 1 1-one

500 mg (7-chloro-1 — (2-difluoromethylphenyl) — 2H — J, 45.0 mg (0.15 mmol) of 2 — (27.3%, 17.0 mg) prepared in Step B of Example 1 A mixture of acetic acid (0.075 mmol) and 713 mg of sodium butyrate was suspended in 15 mL of ping and 0.5 3 3 mL (6.39 mmol) of pyrrolidine was added for 1 hour. After the reaction solution was cooled, ethyl acetate was added. The residue obtained after extraction with 35 sodium sulfate and concentration was purified with a silica gel column ·· hexane = 1: 5) to obtain 7 7.9 mg (7-pyrrolidine-1 -yl-3-(2-3) of solid Set 2 Η Iso D Quilin-1 pay. J-NMR (270MHz, CDC13) δ (ppm) 4H, m), 3.40-3.45 (4H, m), 6.44 (--7.04 (1H, dd, J — 2.6 5 8.6 H z), 7.42-m), 7.78-7.81 (lH, d, J = 7.9Hz), 8 ·) EI-MSm / z 358 (M +) 〇1.54 mmol) Keto I phosphinyl) biphenyl, (7.42 mmol) [A, in this, and then stirred under reflux 2]. The extract was extracted by: chromatography (yellow methylphenyl with 50% ethyl acetate): 2.04-2.09 (1 Η, s), 7.00-7.67 (5.5 Η, 29 (0.5 Η, brs -75- 200536830) (71) The compounds shown in the following examples (Examples 5 to 16) were synthesized by using the compounds obtained in Example 1, Example 2, or Example 3 as starting materials in a similar manner to Example 4. [Example 5] 3-Phenyl-7-pyrrolidine-1, 1Hyl-2H-isoDquinolinone-1-one

〇. W-NMR (270MHz, CDC13) δ (ppm): 2.02-2.12 (4H, m), 3.40-3.45 (4H, m), 6.73 (lH, s) »7.02 (lH, dd, J = 2.6, 8.9Hz ), 7.37-7.51 (5H, m), 7.59-7.65 (2H, m), 8.83 (lH, brs) ESI (LC-MS positive) m / z291 (M + H).

7 — Π is slightly more than a 1-1-3-(2-difluoromethoxyphenyl)-2H_ isoquinoline-1-a ketone

] H-NMR (270MHz, CDCls) 5 (ppm): 2 • 00 — 2.11 (4 Η, m), 3.39 — 3.4 7 (4H, m), 6.64 (1H, s), 7.02 (1H, dd, J = 2.6, 8 · 6Ηζ), 7.3 7-7.5 0 (5H, n), -76- 200536830 (72) 7 · 57— 7.61 (lH, m), 8.60 (; iH, brs) ESI (LC— MS positive) m / z375 (M + H).

[Example 7] 7-morpholine- 4-yl- 3-(2-trifluoromethylphenyl)-2H morpholine-1-one ketone-isoquinone

〇

] H-NMR (500 MHz, CDC13) c5 (ppm): 3.30-4H, m), 3.89-3.91 (4H, m), 6.46 (lH, m)-7.37 (1H, dd, J = 2.3, 8.7Hz ), 7.49-7.51 (, J = 8.7Hz), 7.53-7.67 (3H, m), 7.79—7.8, m), 8.54 (1H, brs) EI-MSm / z 374 (M +). [Example 8] 7-morpholine- 4-yl- 3 -phenyl- 2H-isoquinoline- 1-one ke0. ] H-NMR (270MHz, CDC13) δ (ppm): 3.3 1 (, J = 5.8Hz), 3.91 (4H, t, J = 4.8Hz), 6.73 (), 7.36 (lH, dd, J = 2.6, 8.9Hz) ^ 7.4 1-7.64

3.32 (, 7.35 1H, d 1 (2H 4H, t 1H, s (6H, -77- 200536830 (73) m)), 7.79 (lH, d, J = 2.6Hz), 8.84 (lH, brs) ESI ( LC-MS positive type) m / z307 (M + H). [Example 9] 7-Morlin-4 4-yl- 3-(2-dichloromethoxyphenyl) -2H-isoquinoline-1 Monoketone

1H-NMR (270MHz, CDC13) (5 (ppm): 3.32 (4Η, m

), 3.90 (4H, m), 6.65 (lH, brs) ^ 7.3 5-7.65 (6H, m), 7.80 (lH, d, J = 2.6Hz), 8.60 (lH, brs) ESI (LC-MS positive Type) m / z391 (M + H). [Example 1 〇]

7-piperidine- 1-yl-3— (2-trifluoromethoxyphenyl) -2H-iso-D-Quelin-1 1

] H-NMR (2 70MHz, CDC13) δ (ppm): 1.5 9-1.74 (6H, m), 3.31-3.35 (4H, m), 6.44 (lH, s), 7.36 —7.65 (5H, m ), 7.80—7.81 (2H, m), 8.3 7 (1H, brs) -78- (74) 200536830 ES-MSm / z372 (M +). [Example 1 1] 3-phenyl-7-piperidine-1, 1-yl, 2H-isoDquinoline-1, 1-ketone

'H-NMR (270 MHz, CDC13) 5 (ppm): 1.55 6H, m), 3.33 (4H, t, J = 5_4Hz), 6.71 (1) 7.37 (1H, dd, J = 2.7, 8.9Hz) , 7.40-7.5 5 (, 7.59-7.64 (2Η, η), 7.79 (lH, d, J = 2 8.65) 1H, brs) ESI (LC-MS positive type) m / z305 (M + H [Example 1 2] 7-Diodin-1-1-yl-3— (2-difluoromethoxyphenyl) quinoline-1 monoone—1.80 (3, s), 4H, m) • 7Hz), 2H —different

H-NMR (270MHz, CDC13) δ (ppm): 1.62 2 Η, m), 1 · 7 1 — 1. 7 7 (4 Η, m), 3 · 3 3 (4 Η 5.4 Hz), 6.62 (1Η, s), 7.3 6 — 7 · 5 8 (5 Η, m (1Η, dd, J = 2.0, 7.2Hz), 7.80 (1Η, d, J = -1.66 (, t, J =), 7.59 2.4Hz) -79- 200536830 (75), 8.73 (1 Η, brs) ESI (LC-MS positive type) m / z 389 (M + H). [Example 1 3] Koubayashi 1 7 Mono (4-methylpiperazine- 1-yl)-3-phenyl- 2H-isoD-quinone

. 3H, s 4.8Hz -7.65 ί 5 brs] H-NMR (270MHz, CDC13) 5 (ppm): 2.38 (), 2.62 (4H, t, J = 4.8Hz), 3.38 (4H, t, J =), 6.73 (lH, s), 7.35-7.54 (5H, m) ^ 7.62 (2H, m), 8.00 (lH, d, J = 2.6Hz), 9.09 (11) ESI (LC-MS positive) m / z320 (M + H).

[Example 1 4] Linyi 1 7- (benzylmethylamino)-3-phenyl-2H-isoD-quinone

^ -NMR (27 0MHz ^ CDC13) δ (ppm): 3.15 (), 4.67 (2H, s), 6.73 (lH, brs), 7.10-7.55

3H, s (10H -80- (76) 200536830, m), 7.57-7.70 (3H, m), 9.19 (lH, brs) ESI (LC-MS positive type) m / z341 (M + H). [Example 1 5] 7- (2-morpholine-4-ylethylamino) -3-phenyl-1 2H-isoline-1-one

] H-NMR (270MHz ^ CDC13) (5 (ppm): 2.50 (4H, t, J = 4.6Hz), 2.69 (2H, t, J = 5.8Hz), 3.31 (2H, m), 3.74 ( 4H, t, J = 4.6Hz), 4.71 (lH, brs), 6.71 (1H, s), 7.06 (1H, dd, J = 2.3, 8.6Hz), 7.3 8- 7.51 (5H, m), 7.6 0 — 7 · 6 3 (2 H, m), 8.94 (1H, brs

ESI (LC-MS positive type) m / z350 (M + H). [Example 1 6] 7- (2-morpholine- 4-ylethylamino) -3-(2-trifluoromethoxyphenyl) -2H-isoD-quelin-1-1

H-NMR (400MHz, CDC13) δ (ppm): 2.50 (4H, .37 200536830 (77) brs), 2.69 (2 Η 5 t, J = 6.0Hz), 3.31 (2H, q, 4.2Hz) , 3.74 (4H, t, J = 4.6Hz), 4.73 (1H, brs) 6.62 (lH, s), 7.06 (lH, dd, J = 2.8, 8.4Hz), 7 —7.50 (5H, m), 7 · 5 8 (1 H, dd, J = 1 · 8, 7 · 4 H z) 8.64 (1H ^ brs) ESI (LC-MS positive type) m / z434 (M + H).

[Example 1 7] 7 — [Methyl (2-morpholine-4-ylethyl) amino] -3-Benzene 2 hydrazone-Isoquinoline-1 1-one

14.7 mg (0.024 1 mmol) of 7 —Moryl—4-ylethylamino] —3-phenyl-2H—isoD-Quilin—obtained from Example 15 in 0.5 mL of methanol After adding 0.05 mL of acetic acid and 13.2 (0.168 mmol) of sodium cyanotrihydroborate, the mixture was stirred at room temperature for 6 hours, saturated sodium bicarbonate was added, and extraction was performed with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the residue obtained after concentration under reduced pressure was purified by silica gel tube chromatography (chloromethane: methanol = 20: 1) to obtain 12.8 mg (84%) of 7- [methyl ( 2-morpholine-4 4-ylethyl) amino] -1: phenyl-2H-isoDquinoline-1one.

W-NMR (2 70MHz, CDC13) 5 (ppm): 2.52 (4H, J = 4.6Hz), 2.59 (2H, t, J = 7.3Hz), 3.10 (3Η (2 mg sulfur color, t , S -82- (78) 200536830), 3.61 (2H, t, J = 7.3Hz), 3.72 (4H, t, J = 4.6Hz), 6.73 (lH, brs), 7.19 (lH, dd, J = 2.8, 8.7 Hz), 7.38-7.66 (7H, m), 9.10 (lH, brs) £ 31 (1 ^ -1 ^ 3 positive type) 111/7 364 () ^ +: 9). [Example 1 8] 7 — [methyl (2-morpholine-4 monoethylethyl) amino] -3 — (2-tri

Fluoromethoxyphenyl) -1 2H-isoquinoline-1 1-one

The 7- (2-morpholine-4-ylethylamino) -3- (2-trifluoromethoxyphenyl) -2H-isoDquinoline-1-one obtained in Example 16 was used as the initiator. The starting materials were synthesized by a reaction similar to that in Example 17.

H-NMR (2 70MHz, CDC13) &lt; 5 (ppm): 2.52 (4H, t, J = 4.6Hz), 2.59 (2H, t, J = 7.2Hz), 3.10 (3H, s), 3.61 (2H, t, J = 7.0Hz), 3 • 72 (4H, t, J = 4.6 H z), 6.63 (1H, brs), 7.18 (1H, dd, J = 2.8, i 8.8Hz) 1 7.37 -7. 50 (4H, m), 7.57-7.60 (2 H, m), 8.65 (1 H, s) ESI (LC — MS positive) m / z44 8 (M + H). [Example 1 9] -83- (79) 200536830 7 — [Methyl (2-morpholine-4 monoylethyl) amino] — 3 — (2-trichloromethylphenyl) -2H-iso D Kui commanded 1—reward,

After performing a reaction similar to that in Example 4, a reaction similar to that in Example 17 was performed and synthesized.

W-NMR (270MHz, CDC13) 5 (ppm): 2.5 1-2.6 1 (6H, m), 3.10 (3H, s), 3.59-3.64 (2H, m), 3.70-3.74 (4H, m) , 6.44 (lH, s), 7.16-7.21 (lH, dd, J = 3.0, 8.9Hz), 7.44-7.47 (lH, d, J = 8.91Hz),

7.52— 7.67 (4H, m), 7.78-7.81 (lH, m), 8.32 (1H, brs) ESI (LC-MS positive type) m / z432 (M + H). [Example 20] 7- (4-hydroxymethylpiperidine- 1-yl) -3- (2-trifluoromethylphenyl)-2H-isoDquinoline- 1-one

HO XJN at 400 mg (1.24 mm ο 1) 7-Chloro-3— (2-Dichloromethylphenyl) —2H—Isoquinine—1— Ketone, 4 2 7.2 mg (3.78 mm ο 1) of 4-piperidine methanol, 2 9 · 2 mg (-84- (80) 200536830

0.074 mmol) of 2-dicyclohexylphosphino- 2 / — (N, N-dimethylamino) biphenyl, 28.3 mg (0.0309 mmol) of tris (diphenylmethyleneacetone) dipalladium To the mixture was added 8.65 mL (8.65 mmol) of a 1 M solution of lithium bis (trimethylsilyl) fluorenamine in THF, and the mixture was stirred under reflux for 1 night. After the reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by concentrating the extract was purified by silica gel column chromatography (—Qiyuanyuan: Methanol = 2 5: 1 ~ 2 0: 1) to obtain 3 5 5 · 6 mg (71%) of a brown solid — 7 — (4-hydroxymethylpiperidine- 1-yl) —3- (2-trifluoromethylphenyl) —2H—isoquinoline-1—one. ] H-NMR (270MHz, DMSO-d6) 5 (ppm): 1.27 (2H, dq, J = 3.5, 12.1Ηζ), 1.49— 1.67 (1H, m), 1.72-1.83 (2H, m), 2.76 (2Η, dt, J = 2.0, 12.2Hz), 3.25-3.35 (2H, m), 3.78-3.89 (2H, m), 4.51 (lH, t, J = 5.3Hz), 6.37 (1h, s), 7.43-7.60 (4H, m), 7.61— 7.80 (2H, m), 7.85 (lH, d, J = 7.6Hz), 1 1.3 8 (1H, brs) ESI (LC- MS positive) m / z403 (M + H). The compounds shown below (Examples 21 to 37) were synthesized using the compounds obtained in Example 1, Example 2 or Example 3 as starting materials, and synthesized in a similar manner to Example 20. [Example 2 1] 7- (4-methylmethylpiperidine-yl) -3-phenyl-2H-isoquine-85-200536830 (81) Linyi 1

h〇XjN ο] H-NMR (270MHz, CDC13) (5 (ppm): 1.43 (2H, dq, J = 4.0, 12.2Hz), 1.48-1.56 (1H, m), 1.63-1.81 (lH, m) , 1.90 (2H, d, J = 14.2Hz), 2.86 (2H, dt

, J = 2.3 ^ 12.2Hz), 3.45—3.65 (2H, m), 3.86-3.96 (2H, m), 6.73 (lH, s), 7.38 (lH, dd, J = 2.6, 8.9Hz ), 7.42-7.53 (4H, m), 7.63-7.69 (2H, m), 7.81 (lH, d, J = 2.6Hz), 9.08 (lH, brs) ESI (LC-MS positive) m / z335 ( M + H). [Example 22] 7- (4-Hydroxymethylpiperidine- 1-yl) -3- (2-trifluoromethoxyphenyl)-2H-isoxorphyrin- 1-one

] H-NMR (270MHz, CDC13) (5 (ppm): 1.25- 1.48 (3H, m), 1.74 (lH, m), 1.89 (2H, d, J = 13.2Hz), 2.87 (2H, dt, J = 2.4, I2.2Hz), 3.57 (2H, t, J = 5.4Hz), 3.93 (2H, d, J = 12.7Hz), 6.33 (lH, s), -86- (82) 200536830 7.37— 7.59 ( 6H, m), 7.82 (lH, d, J = 2.4Hz), 8.60 (1 Η, brs) ESI (LC-MS positive type) m / z419 (M + H). [Example 2 3] 7 — (3-hydroxymethylpiperidine-1 1-yl) -3-(2-trifluoromethylphenyl) -2H-isoquinoline-1 1-ketone

〇

j-NMR (270MHz, CDC13) 5 (ppm): 1.61- 1.33 (lH, m), 1.60-2.05 (5H, m), 2.73 (lH, dd, J = 9.9, 12.2Hz), 2.90 (1H, dt , J = 3.0, 11.7 Hz), 3.55-3.81 (3H, m), 3.83-3.93 (lH, m), 6.45 (lH, s), 7.41 (1H, dd, J = 2.3, 8.6Hz), 7.43— 7.70 (4H, m

), 7.75— 7.84 (2H, m), 8.58 (1H, brs) ESI (LC-MS positive type) m / z403 (M + H). [Example 24] 7- (3-Amino group via a methyl group) —3-Phenyl-2H-isoD-quinoline-1H

〇 -87- (83) (83)

200536830 1H-NMR (270 MHz, CDC13) 5 (ppm): 1.23-1

lH, m): 1.64—2.07 (5H, m), 2.72 (2H, dd, J, 12.2Ηζ), 2.89 (lH, dt, J = 3.0, 12.2 Hz), 3. 3.79 (3H, m) , 3.90 (lH, dd, J = 3.5, 12.2Hz 6.72 (lH, s), 7.35-7.52 (5H, m), 7.59-7.65, m), 7.82 (lH, d, J = 2.6Hz), 9.23 (lH, brs) ESI (LC-MS positive type) m / z335 (M + H). [Example 2 5] 7- (3-hydroxymethylpiperidine-1-yl) -3- (2-trifluoromethylphenyl)-2H-isoD-Quilin-1

.32 (-9.9 .53 —), (2H oxygen

] H-NMR (270MHz, CDC13) δ (ppm): 1.20-1. LH, m), 1.69-1.75 (lH, m), 1.82--1_88 (3H,, 1.94-2.01 (lH, m) , 2.73 (lH, dd, J 2 10 12.4 Hz), 2.90 (2H, dt, J = 2.8, 11.2 Hz), 3. 3.70 (2H, m), 3.76 (lH, d, J = 12.8 Hz), 3.90, dd, 4.0, 12.0 Hz), 6.63 (1H, s), 7.37-7.50, m), 7.58 (lH, dd, J = 1.6, 7.6 Hz), 7.82 (1 :, J = 2.4 Hz), 8.82 (1H, brs) ESI (LC-MS positive type) m / z419 (M + H). 28 (m) 丨 · 4, 58-(1Η (5Η Η, d -88- 200536830 (84) [Example 2 6] Trifluoromethylbenzene 7- (2-hydroxymethylpiperidine-1-yl ) —3— (Base) —2H—IsoD Quinoline—1

j-NMR (270MHz, CDC13) 5 (ppm) 6H, m), 2.04-2.07 (lH, m), 3.12-3

, 3.63— 3.68 (2H, m), 3.86— 3.93 (1H 4.15 (lH, m), 6.45 (lH, s), 7.39-7. J = 2.31, 8.91Hz), 7.45— 7.48 (lH , D ,, 7.52-7.67 (3H, m), 7.78-7.81 (1H, 7.86 (lH, d, J = 2.31Hz), 8.54 (lH, bri

El (positive) m / z402 (M +). [Example 2 7] 7-(2-1-yl via methylmethyl group D)-3-benzophenone-1 monoketone: 1.64-1.8 0 (• 20 (1 Η, m), m) 5 4.12 — 43 (1H, dd, J = 8.58Hz), m), 7.85 — o base—2 H — isokou

j-NMR (270 MHz, CDC13) δ (ppm): 6H, m), 2.35 (lH, brs), 3.10-3.22

3.60— 3.73 (2H, m), 3.89 (lH, dd, J 1.60—1.8 8 ((1 H, m)): 6.9, 1 0.9Hz -89- 200536830 (85)), 4.06—4.18 (lH , M), 6.71 (lH, s), 7.35-7.52 (5H, m), 7.60-7.65 (2H, m), 7.85 (lH, d, J = 2.6Hz), 9.33 (1H, brs) ESI (LC -MS positive type) m / z335 (M + H). [Example 2 8] 7— (2-hydroxymethylpiperidine-1—yl) —3— (2-trifluoromethoxy

Phenyl)-2H-isoD-Quelin-1 1

] H-NMR (270MHz ^ CDC13) 5 (ppm): 1.61- 1.80 (6H, m), 1.94-1.95 (lH, m), 3.12-3.20 (1Η, η), 3.65-3.73 (2H, m), 3.87-3.93 (lH, m) ^ 4.13- 4.16 (lH, m), 6.62 (lH, s), 7.37-7.51 (5Η, η)

, 7.5 7-7.60 (1 H ^ m), 7 · 8 5 — 7 · 8 6 (1H, d, J = 2.31Hz), 8.71 (1H, brs) EI (LC— MS positive type) m / z418 ( M +). [Example 29] 7- (4-hydroxypiperidine-1-yl) -3- (2-trifluoromethylphenyl)-2 hydrazone-isoD-Querin-1 1-fluorene -90- (86) 200536830

] H-NMR (270MHz ^ CDC13) 5 (ppm): 1.6 3-1.8 0 (3H, m), 1.98— 2.11 (2H, m), 3.08 (2H, ddd, J = 3.0, 9.9, 12 · 9Ηζ), 3.67—3.80 (2H, m), 3.85—3.98 (lH, m), 6.45 (lH, s), 7.38 (lH, dd, J = 2.6,

8.9Hz), 7.43-7.68 (4H, m), 7.77-7.83 (2H, m), 8.55 (1H, brs) ESI (LC-MS positive type) m / z389 (M + H). [Example 3 0] 7-(4-hydroxypiperidine-1 monoyl) -3 -phenyl-2H-isoDquinoline_1 monoone

JH-NMR (270MHz, CDC13) (ppm): 1.5 8 — 1.8 0 (3H, m), 1.98-2.11 (2H, m), 3.03-3.15 (2H, m), 3.68-3.79 (2H, m), 3.85 — 3.98 (lH, m), 6.72 (1H, s), 7.38 (1H, dd, J = 2.6 ^ 8.9Hz, 7.4 3-7.5 3 (4H, m), 7.60-7.65 (2H, m ), 7_81 (lH, d, J = 2.6Hz), 8.83 (1H, brs) ESI (LC-MS positive type) m / z321 (M + H). -91-(87) 200536830 [Example 3 1] 7— (4-hydroxypiperidine-1—yl) —3— (2-trifluoromethoxyphenyl) —2 fluorene —isoDquinoline-1—one

] H-NMR (270MHz, CDC13) δ (ppm): 1.5 1 (1 (, d, J = 4.4Hz), 1.72 (2H, m), 2.05 (2H, m), 3.10 (2H, m), 3.70 ( 2H, m), 3.80— 3.90 (lH, m) ^ 6.60 (lH, brs), 7.40— 7.60 (6H, m), 7.80 (lH, d, J = 2.4Hz), 8.60 (1H, brs) ESI (LC-MS positive) m / z405 (M + H). [Example 3 2] 7- (3-1-based via base pulse D)-3-(2-difluoromethylphenyl)-2 Η-isopropaneline-1-wake up

Ο

] H-NMR (270MHz ^ CDC13) δ (ppm): 1.60-1.80 (2H, m), 1.82-2.02 (2H, m), 2.13-2.21 (lH, m), 3.22 (1H, dd, J = 6.1 , 1 2.7Hz), 3.18— 3.37 (2H, m), 3.52 (1H, dd, J = 3.0, 12.2Hz) ^ 3.92-4.03 (-92- 200536830 (88) lH, m), 6.45 (lH, s ), 7.39 (lH, dd, J = 8.6Hz), 7.42-7.70 (4H, m), 7.81 (lH, dd, brs), 9.2Ηζ), 7.84 (lH, d, J = 2.6Hz) , 8.48 (1H, ESI (LC-MS positive) m / z389 (M + H). [Example 3 3] 7- (3-hydroxypiperidine- 1-yl)-3-phenyl-2H-iso Quinine

-ketone

W-NMR (270MHz, CDC13) 5 (ppm): 1.50- 1

2H, m), 1.82-2.05 (2H, ni) ^ 2.09-2.18 (1H, 3.20 (1H, dd, J = 6.8, 12.0Hz) ^ 3.18-3.35 (m), 3.51 (1H, dd, J = 3.1 , 1 2.0Hz), 3.92— 4

1H, m), 6.72 (1H, s), 7.38 (1H, dd, J = 8.9Hz), 7.41-7.53 (4H, m), 7.5 8-7.64 (2H, 7.83 (lH, d, J = 2.6Hz), 8.85 (lH, brs) ESI (LC-MS positive type) m / z321 (M + H). [Example 3 4] 7- (3-Hydroxypiperidine-1 1-base)-3— (2-trifluoromethoxy) —2 Η Iso-D Quilin-1 1 嗣 • 80 (, m) 2H, • 02 (2.6,, m) phenyl-93- 200536830 (89 )

j-NMR (270 MHz, CDC13) δ (ppm): 1.6 5 — 1.7 5 (2H, m), K76 — 1.94 (2H, m), 2.06 (lH, d, J = 7.3Hz), 3.18- 3.34 (3H, m), 3.52 (lH, dd, J = 2.9, 12.2Hz), 3.98 (1H, m), 6.60 (1H, s), 7.30-

7.60 (6H, m), 7.84 (lH, d, J = 2.4Hz), 8.60 (1H, brs) ESI (LC-MS positive type) m / z405 (M + H). [Example 3 5] 7 — (3-hydroxypyrrolidine- 1-yl) — 3 — (2-trifluoromethylphenyl) — 2 Η —iso-D-quinine — 1 —

j-NMR (270MHz, DMSO — d6) 5 (ppm): 1.97-

2.13 (2H, m), 3.16-3.20 (1Η, η〇, 3.38-3.55 (3H, m), 4.4-4.5 (lH, m), 5.02-5.03 (lH, d, J = 3.0Hz), 6.35 (lH, s), 7.04-7.07 (lH, m), 7.01-7.2 (lH, m), 7.50-7.53 (lH, d, J = 8.58Hz), 7.58-7.61 (lH, d, J 7.26Hz), 7.64-7.78 (2H, in), 7.83-7.86 (1H, d, J = 7.92Hz), 11.3 (1H, brs) -94- 200536830 (90) EI — MS m / z 3 7 4 (M +). [Example 3 6] Isoquinoline

7 — (3 once through Kirallein 1 1 — 3 —phenyl — 2H — 1 monoketone

! H-NMR (270 MHz, DMSO — d6) δ (ppm): 2.00 (lH, m), 2.00-2.18 (lH, m) ^ 3.15-3

M), 3.30—3.550 (2Η, η), 3.52 (lH, dd, J 10.4Hz), 4.40 — 4.50 (1H, m), 5.03 (1H, 3.6Hz), 6.84 (lH, s), 7.06 (lH, dd, J = 2.6

), 7.15 (lH, d, J = 2.6Hz), 7.32-7.50 (3H 7.57 (1H, d, J = 8.6 · ζ)), 7 · 7 2-7 · 8 0 (2H, 1 1.24 (1H , M) ESI (LC-MS positive type) m / z30 7 (M + H). [Example 3 7] 7 — (3-hydroxypyrrolidine-1 —yl) — 3 — (2 -trifluoro) -2H-isoDquinoline-1-one 1.88-.20 (1H = 4.8, d, J =, 8.9Hz, m), m), oxybenzene

-95- 200536830 (91)] H-NMR (270MHz, DMSO — d6) δ (ppm): 1.97 (1H, brs), 2.06 — 2.12 (1H, m), 3.18 (1H, d, J: 9.6Hz) , 3.37—3.45 (2H, m), 3.50—3.54 (lH, m), 4.45 (lH, brs), 5.02 (lH, d, J = 3.2Hz), 6.54 (lH, s), 7.06 (lH, dd) , J = 2.4, 8.8 Hz), 7.15 (1H, s), 7.46-7.65 (5H, m), 11.30 (lH, s) ESI (LC-MS positive type) m / z391 (M + H).

[Example 3 8] 7-Amino-3- (2-trifluoromethylphenyl)-2H-isoD-quinoline- 1-one

0

H2N at 2.50 g (7.72 mmol) of 7-chloro-3- (2-trifluoromethylphenyl) -2H-isoquinoline-1 monoketone prepared in step B of Example 1, 64.9 mg (0.1 85 mmol) of 2- (dicyclohexylphosphino) biphenyl and 70.7 mg (0.0772 mmol) of tris (diphenylmethyleneacetone) dipalladium was added to a mixture of 21 ml (21 mmol) ) Solution of 1 M lithium bis (trimethylsilyl) fluorenamine in THF, and stirred under heating and refluxing for 1 night. After the reaction solution was cooled to room temperature, 63 mL of 1N hydrochloric acid was added, and the mixture was stirred for 5 minutes. The reaction solution was neutralized with 8 mL of a 5N aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was washed with saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by concentrating the extract was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1 ~ 6: 丨) to obtain 2 · 4 g (9〗%) of a brown solid-96- 200536830 ( 92) of 7-amino-3- (2-trifluoromethylphenyl)-2H-isoD-quinolinone-1-one. H-NMR (270 MHz, CDC13) (5 (ppm): 4.00 (2H, brs), 6.43 (lH, s), 7.07 (lH, dd, J = 2.5, 8.3 Hz), 7.40 (1 H, d, J = 8 · 3Ηζ), 7 · 5 0-7 · 6 9 (4 H, m), 7.76 — 7.83 (lH, m), 8.63 (1H, brs) ESI (LC-MS positive) m / z305 (M + H).

The compounds shown below (Examples 39 to 40) were synthesized by using the compounds obtained in Example 2 or Example 3 as starting materials in a similar manner as in Example 38. [Example 3 9] 7-Amino-3 -phenyl-2H-isoquinolin-1-one

〇 h2n

] H-NMR (270MHz, DMSO — d6) δ (ppm) ··· 5.5 7 (2H, brs), 6.75 (1H, s), 7.01 (1H, dd, J = 2.7, 8.1Hz), 7.28-7.49 ( 5H, m), 7.73 (2H, d, J = 8.9Hz), 1 1.10 (1H, brs)

El (positive) m / z 23 6 (M +). [Example 40] 7-Amino-3-(2-trifluoromethoxyphenyl)-2H-isoDquinoline- 1 -97- 200536830 (93)

] Ν-NMILI (270 ΜΗζ, 〇〇 (: 13) δ (ppm): 4.03 (2Η, brs), 6.62 (lH, s), 7.07 (lH, dd, J = 2.5, 8.4Hz), 7.35- 7.52 (4H, m), 7.58 (1H, dd, J = 2.0, 7.3Hz), 7.66 (lH, d, J = 2.3Hz), 8.80 (lH, brs) ESI (LC-MS positive) m / z321 (M + H). [Example 4 1] 7- (2-hydroxyethylamino) -3- (2-trifluoromethylphenyl)-2H-isoD-quinoline-1-one, and 7 — [Bis (2-hydroxyethyl) amino] — 3 — (2-trifluoromethylphenyl) —2H —isoDquinoline—1—one

and

3 50 mg (1.15 mmol) of the 7-amino-3- (2-trifluoromethylphenyl) -2H-isophosphonyl-1 monoketone obtained in Example 38 was dissolved in 1 1.5 m L of methanol, add 1.15 m L of acetic acid and 5 5 2.5 mg (4.60 mmol) of glycolaldehyde dimer. After adding 722 mg (1 1.5 mmol) of sodium cyanotrihydroborate in an ice bath, the mixture was warmed to room temperature and stirred for 8 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated. The obtained residue is a silicone tube -98- (94) (94)

200536830 column chromatography (dichloromethane: methanol = 2 0: 1 ~ 1 2: 1) yellow amorphous 61.8 mg (15%) of 7— (2 —) —3— (2-trifluoromethylbenzene) A) 2H-isoD-quinone, 3 6 9.3 mg (82%) of 7-ylethyl) amino group as a yellow foamy substance] a 3-(2 -trifluoromethylphenyl H Lin-1 -1 .

7- (2-hydroxyethylamino) -3- (2-trifluoroI 2H-isoquinoline-1 1-ketone W-NMR (270MHz, CDC13) δ (ppm) brs), 3.46 (2H, t, J = 5.6Hz), 3.86—3 ·, 4.42 (lH, brs), 6.44 (lH, s), 7.07 (2.6, 8.6Hz), 7.41 (1H, d, J = 8.6Hz),

4H, m), 7.78 — 7.82 (lH, m), 8.36 (1H ESI (LC—MS positive) m / z 349 (M + H). 7 — [bis (2-hydroxyethyl) amino] — 3- (2 —) —2 Η—isoD quinine—1—j-NMR (2 70MHz, CDC13) 5 (ppm) brs), 3.71 (4H, t, J = 4.9Hz), 3.94 (

4.9Hz), 6.43 (lH, s), 7.19 (lH, dd, J), 7.43 (lH, d, J = 8.9Hz), 7.49-7.68 7.63 (lH, d, J = 7.6Hz), 8.56 (1H, brs) ESI (LC — MS positive) m / z 393 (M + H). Purified to obtain the ethyl ethylamino p-1 monoketone and-[bis (2-hydroxy) -2 fluorene-isoquinsylphenyl)-: 1 · 7 9 (1 Η, 95 (2Η, m ) 1H, dd, J = 7.49-7.69 (,, brs) trifluoromethylphenyl: 3.59 (2H,: 4H, t, J bis = 3.0, 8.9Hz (4H, m), -99- 200536830 (95) The mouthpieces shown below (Example 4 2 to Example 4 5) are based on Example 3 8 1 Example 3 9 ㉟ Implementation ㈣ 4 pounds of compound obtained as starting materials, basis and examples 41 was obtained by a similar method. [Example 4 2] 7 ^ 2hydroxyethyl) amino-3 ~ phenyl-2H-isoquinoline-1 1

Ketone 1 difluoroacetate, and 7- [bis (2-hydroxyethyl) amino]-3 -phenyl- 2H-isophosphon-1-one

After purification of 7- (2-hydroxyethyl) amino-3-phenyl-2H-isoquinoline-1-one ketone trifluoroacetate in the same manner as in Example 41, a portion was removed and analyzed by HPLC. (ODS-80TS 55x300mm, acetonitrile: aqueous solvent is used as the eluent) and purified.

7 — (2-hydroxyethyl) amino — 3 —phenyl — 2H-isoquinoline — 1 monoketone 1 trifluoroacetate

] H.NMR (270MHz ^ DMSO- d6) 5 (ppm): 3.21 (2H

, T, J = 5.9Hz), 3.59 (lH, t, J = 5.0Hz), 3.61 (2H, t, J = 5.9Hz), 3.85 (2H, brs), 6.79 (1H, s), 7 · 12 (1H, dd, J = 2.4, 8.4Hz), 7.22-7 · 24 (1H, m), 7.3 5-7.5 6 (4H, ni), 7 · 7 2—7 · 7 6 (2H, m), 1 1.20 (1 H, brs) ESI (LC — MS positive) m / z281 (M + H—TFA). -100- 200536830 (96) 7 — [bis (2-hydroxyethyl) amino] -3-phenyl-2H-isoquinoline-1-one 1H-NMR (270MHz, DMSO — d6) 5 (ppm) : 3.45- 3.63 (8H, m), 4.84 (2H, m), 6.81 (lH, s), 7.18-7.25 (lH, m), 7.33-7.57 (5H, m), 7.70-7.79 (2H, m), 1 1 .22 (1 H, brs)

ESI (LC-MS positive type) m / z325 (M + H). [Example 43] 7- (2-hydroxyethylamino) -3- (2-trifluoromethoxyphenyl)-2H-isoDquinoline-1 1-ketone, and 7- [bis (2- Hydroxyethyl) amino]-3- (2-trifluoromethoxyphenyl)-2H-isoquinoline-1 monoketone

7- (2-Ethylethylamino) -3- (2-difluoromethoxyphenyl)-2H-isoquinoline-1 1-ketone] H-NMR (270MHz, CDC13) 5 (ppm): 1.70 (1H, brs), 3.46 (2H, t, J = 5.1Hz), 3.88-3.95 (2H, m), 4.40 (lH, brs), 6.62 (lH, s), 7.06 (lH, dd, J =

2 · 6, 8.6Ηζ), 7.35—7.50 (4H, m), 7.54 (lH, d, J = 2.6Hz), 7.58 (lH, dd, J = 1.7, 7.3Hz), 8.59 (1Η , Brs) -101-

200536830 (97) ESI (LC-MS positive) η / ζ 365 (M + Η). 7 — [Bis (2-hydroxyethyl) amino] —3— (2-trifluoromethoxy) —2H—isoD-Quulin—1—wake up] ΝNMIL (270MHz, CDC13) δ (ppm) : 3.50—3 8H, m), 4.84 (2H, t, J = 5.1Hz), 6.53 (lH, s 7.23 (1 H, dd, J = 2.6, 8.9Hz)), 7.37 (1H, d, 2.6Hz) , 7.43-7.64 (5Η, m), 11.28 (1H, s) ESI (LC-MS positive type) m / z409 (M + H). [Example 44] 7- (2-hydroxyethyl Amino group) -3- (2-trifluoromethoxy) -2H-isoD-quinoline-1 1-ketone, and 7- [bis (2-methoxyethylamino) -3-phenyl-2H -Isoquinoline-1, one ketone, 7- (2-hydroxyethylamino), 3- (2-trifluoromethoxyphenyl, 2 Η-isoDquinoline-1, one-ketone] H-NMR (270MHz, CDC13) 5 (ppm): 3.40- 3.5.5H, m), 3.65—3.69 (2H, t, J = 4.95Hz), 4.0 · 5Η, brs), 6.71 (1Η, s), 7 · 0 2-7 · 0 6 (1 H, m 7 · 32— 7. · 51 (5 · 5Η, η), 7.59— 7 · 62 (2Η, π〇, 8. · 0.5H, brs) phenylbenzene • 65 (;), 'J diphenylyl)) 50 (39 (), 86 (-102- 200536830 (98) EI- MS m / z 2 9 4 (M +). 7- [bis (2-methoxyethyl) amino] -3-phenyl- 2H-isoquinolin-1 1-H] NMR (2 7 0MHz ^ CDC13) 5 (ppm): 3.37 (6H, s), 3 „43— 3.73 (8H, m), 6,71 (lH, s), 7.20—7.24 (lH, dd, J = 2.64, 8 · 91Ηζ), 7.38—7.52 (4H, m),

7.56— 7.57 (1H, d, J = 2.64Hz), 7.60— 7.63 (2H, m), 8.83 (1H, brs) ESI (LC-MS positive type) m / z353 (M + H). [Example 4 5] 7- (2,3-dihydroxyphenylamino)-3-phenyl- 2H-isoDquinoline-1 -one

OH '* 〇] H-NMR (270 MHz, CD3OD) (5 (ppm)): 3.17—3.24

(1H, dd, J = 6.93, 1 3.2Hz), 3.37—3.44 (1H, dd, J = 4.95, 13.2Hz), 3.56--3.69 (2H, m), 3.8 7-3.9 3 (lH, m), 6.84 (lH, s), 7.15— 7.20 (lH, d, J = 2.31, 8.58Hz), 7.38— 7.52 (5H, m), 7.67— 7.70 (2H, m) FAB-MS m / z 311 (M + H). -103- 200536830 (99) [Example 4 6] 7 — [(2,3-dihydroxypropyl) (2-hydroxyethyl) amino] -3—phenyl-1 2 hydrazone—isoD-quelin-1 1 — remuneration

〇Η The 7- (2-hydroxyethyl) amino group obtained in Example 42 was used as a raw material, and a compound similar to that used in Example 41 was used as a raw material. This method yielded 7-[(2,3-dihydroxypropyl) (2-hydroxyethyl) amino] -3-phenyl-2'-isoquinoline-1 monoone. 1 H-NMR (2.7 MHz, CD3OD) (ppm): 3.39- 3.47 (1H, dd, J = 7.92, 15.2Hz), 3.56--3.69 (3H, m),

3.71— 3.88 (4H, m), 3.98—4.07 (lH, m), 6.85 (1H, s), 7.35—7.52 (5H, m), 7.57— 7.60 (lH, d, J = 8.91Hz), 7.66 — 7.70 (2H, m) ESI (LC- MS positive type) m / z355 (M + H). [Example 4 7] 7-[(2-hydroxyethyl) methylamino] -3- (2-trifluoromethylphenyl) -2H-Isoaneline-1 Iso-104 &gt; (100 ) 200536830

473 mg (1.55 mmol) of 7-amino-3- (2-trifluoromethylphenyl)-2H-isoquinoline- 1-one obtained in Example 38 was dissolved in

10 mL of methanol, add 2 mL of acetic acid and 120 mg (1.0 mm) of glycolaldehyde dimer, add 754 mg (12.0 mmol) of sodium cyanotrihydroborate, and stir at room temperature for another 3 hours . Add 0.82 mL (10 mmol) of a 37% aqueous formaldehyde solution and stir for 2.5 hours. After the reaction solution was concentrated, a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate: methanol = 1 5 ·· 3 0: 1) to obtain a yellow color. 3 44 mg (61%) of 7-[(hydroxyethyl) methylamino] -3- (2-trifluoromethylphenyl)-2H-isoquinoline- 1-one as a solid.

j-NMR (270MHz, CDC13) (5 (ppm): 2.12 (1H, brs), 3.12 (3H, s), 3.63 (2H5t, J = 5.8Hz), 3.88 (2H, t, J = 5.8Hz), 6.44 (lH, s), 7.24—7.26 (1H, m), 7.46 (lH, d, J = 8.8Hz), 7.52—7.65 (4H, m), 7_79 (lH, d, J = 8.4Hz), 8.55 (lH, brs) ESI (LC-MS positive) m / z363 (M + H). The compounds shown below (Example 48 to Example 52) are based on Example 3 8. Examples 39 or the compound obtained in Example 40 was used as a starting material and was synthesized by a method similar to that in Example 47. -105- (101) 200536830 [Example 4 8] MD | 7— [(2—Ethyl Ethyl) methylamino]-3-phenyl- 2H — Lin-1

1H-NMR (270MHz, DMSO-d6) 5 (ppm): 3.04, s), 3.51-3.61 (4H, m), 4.77 (lH, brs), 6 lH, s), 7.26 (lH, dd, J = 1.98, 8.91 Hz) ^ 7.34, d, J = 1.98 Hz), 7.38— 7.48 (3H, m), 7.56 (1, J 2: 8.91Ηζ), 7.76 (2H, d, J = 8.25Hz ), 11.2, brs) ESI (LC-MS positive) m / z295 (M + H). [Example 49] 7-[(2-hydroxyethyl) methylamino]-3- (2-trifluoromethylphenyl) -2 Η-isoD.

(3H .83 ((1H H, d (1H oxy

1H-NMR (270 MHz, CDC13) δ (ppm): 2.29 (brs), 3.12 (3H, s), 3.63 (2H, t, J = 5.8Hz), (2H, t, J = 5.8Hz), 6.64 (lH, s), 7.24 (1H, 1H, 3.89 dd, -106- 200536830 (102) J = 2.6, 8.9Hz), 7.33—7.52 (4H, m), 7.59 (lH, dd ,: ί = 1 · 8, 7 · 1Ηζ), 7.64 (2H, d, J = 2.6Hz), 9.00 (1Η, brs) ESI (LC-MS positive) m / z379 (M + H). [Example 5 0]

7-[(2,3-Dihydroxypropyl) methylamino] -3 -phenyl- 2H

Monoisoquinoline-1 monoketone

OH 1 Ο

HO

] H-NMR (400MHz, CD3OD) δ (ppm): 3.14 (3Η, s), 3.42 (1H, dd, J = 7.32, 15.1 Hz), 3.5 5-3.6 9 (3H, m), 3.93-3 · 99 (1Η, π〇, 6.85 (lH, s), 7.34 —

7.42 (2H, m), 7.45— 7.49 (3H, m), 7.58 (lH, d, J = 9.28Hz), 7.66-7.69 (2H, m) FAB-MS m / z 325 (M + H) . [Example 5 1] 7- [Methyl ((2S, 3R) -2,3,4-trihydroxybutyl) amino]-3 -phenyl-2 hydrazone -isoD-Quulin-1 -remuneration

-107- (103) 200536830 W-NMRHOOMHz'CDsOD) δ (ppm): 3.17 (3H, s), 3.36-3.41 (lH, m), 3.54-3.58 (lH, m), 3.63-3.68 (lH, m ), 3.78—3.82 (lH, m), 3.87-3.96 (2H, m), 6.86 (lH, s), 7.38-7.42 (2H, m), 7.46 — 7.50 (3H, m), 7.56 — 7.59 (lH, d, J = 8.79 Hz), 7.68 — 7.70 (2H, m) FAB-MS m / z 355 (M + H).

[Example 5 2] (2-[methyl [1 monooxo-3- (2-difluoromethoxyphenyl) -1,2-dihydroxyisoD-quinolin-7-yl] amine } Ethyl) third butyl carbamate

^ -NMR (270MHz »CDC13) 5 (ppm): 1.45 (9H, s), 3.11 (3H, s), 3.23—3.41 (4H, m), 4.72 (1H, bts), 6.63 (lH, s ), 7.18— 7.25 (lH, m), 7.34—7.50 (4H, m), 7.55-7.62 (2H, m), 8.64 (lH, brs ESI (LC—MS positive) m / z478 (M + H) [Example 5 3] 7-[(2-aminoethyl) methylamino] -3- (2-trifluoromethoxy-108- (104) 200536830 phenyl)-2H-isoD Porphyrin-1, one, one, trifluoroacetate

F F at 455.4 mg (0.954 mmol) of (52-{methyl [1-oxo-3-(2-trifluoromethoxyphenyl) -1,2

2 mL of trifluoroacetic acid was added to a solution of monodihydroxyisoquinoline-7-yl] amino} ethyl) aminocarboxylic acid third butyl ester in 4 mL of dichloromethane, and the mixture was stirred at room temperature for 2.5 hours. A part of the residue obtained after the reaction solution was concentrated was purified by HPLC (ODS-80TS 55x300 mm, acetonitrile: water-based solvent was used as the eluent) to obtain 299.4 mg (52%) of thick green viscous oily substance 7 — [( 2-Aminoethyl) methylamino]-3-(2-trifluoromethoxyphenyl)-2H-isoDquinoline-1 monoone 2 trifluoroacetate ° 1H-NMR (270MHz, DMSO — D6) δ (ppm): 2.95- 3.10 (6H, m), 3.65 (2H, t, J = 6.9Hz), 6.57 (1Η,

s), 7.32 (1H ^ dd, J 2 3.0, 8.9Ηζ), 7.40-7.68 (6H, m), 7.84 (3H, brs), 11.37 (lH, s) ESI (LC-MS positive) m / z 378 (M + H—2TFA). [Example 54] 7- (2-Aminoethylamino) -3-phenyl- 2H-isoquinoline-1-one 2 Trifluoroacetate -109- (105) 200536830

0.5 ml of acetic acid and 337 were added to a solution of 100 mg (0.423 mmol) of 5 ml of 7-amino-3-phenyl- 2 hydrazone-isoD-quinoline-1 monoketone in Example 39 obtained in Example 39. mg (2.12 mmol) of tert-butyl N- (2-oxoethyl) aminoformate, add 140 mg (2.1 2 mmol) of sodium cyanotrihydroborate under ice bath, and stir at room temperature for 1 hour . Then, 40 mg (2.12 mmol) of sodium cyanotrihydroborate was added, and after stirring at room temperature overnight, methanol was distilled off, and a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain about 500 mg of a residue. This residue was dissolved in a mixed solvent of 1 mL of dichloromethane and 1 mL of methanol, and 7 mL of trifluoroacetic acid was added under an ice bath, followed by stirring for 1 hour. The residue obtained after concentrating the reaction solution was dissolved in methanol, and a portion was taken out and purified by HPLC (ODS—80TS 55x300 mm, using water · acetonitrile = 45: 25-0.05% trifluoroacetic acid solution as eluent) to obtain a pale yellow color. 73 mg (34%) of 7- (2-aminoethylamino)-3-phenyl-2H-isoD-quinoline- 1-keto-2 trifluoroacetate as a solid.

W-NMR (270MHz, DMSO-d6) δ (ppm): 3.02 (2H, t, J = 6.2Hz), 3.22—3.43 (6H, m), 6.23 (lH, t, J = 5.5Hz), 6.81 ( lH, s), 7.10 (lH, dd, J = 2.3, 8 · 8Ηζ), 7.26 — 7.29 (1H, m), 7.36 — 7.54 (4H, m), 7.70 — 7.85 (3H, m) ESI (LC-MS positive type) m / z280 (M + H-2TFA). -110- (106) 200536830 [Example 5 5]

7— [(2-Dimethylaminoethyl) methylamino]-3 -Phenyl-2H-IsoD Quilin-1 1

Ο

30 mg (0.05 9 mmol) of 7- (2-monoaminoethylamino) -3-phenyl-2H-isoD-quinoline-1, 1-keto-2 trifluoroacetate in methanol obtained in Example 54 To 5 mL of the solution was added 0.021 mL (0.12 mmol) of diisopropylethylamine, 0.5 mL of acetic acid, 1 mL of a 37% aqueous formaldehyde solution, and 20 mg (2.96 mmol) of sodium cyanotrihydroborate. Stir at room temperature for 1 hour. After distilling off the solvent, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the residue obtained after concentration under reduced pressure was taken out by HPLC (ODS — 80TS 55x300 mm, using water ·· acetonitrile = 4 5: 2 5 — 0.05% trifluoroacetic acid solution as the eluent) Perform purification. Once the obtained compound was dissolved in ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 11 mg (58%) of 7-[(2-dimethylaminoethyl) as a solid. ) Methylamino]-3-phenyl- 2H-isoD-quinolin- 1-one. ] H-NMR (270MHz, CDC13) δ (ppm): 2.24 (6Η, s), 2.46 (2H, t, J = 5.3Hz), 3.02 (3H, s), 3.51 (

2 H 5 t, J = 7.3 H z), 6.65 (1H, s), 7.11 (1H, dd, J = 2.6, 8.5 H z) '7.29— 7.44 (4H' m) '7.50 (1H, d '-111-(107) 200536830 J-2.4Hz), 7.56-7.60 (2H, m), 9.34 (lH, bi * s) ESI (LC-MS positive type) m / z322 (M + H). [Example 5 6] 7 — [(2-Aminoethyl) methylamino]-3-phenyl-1 2H-isoquinoline-1 1-one 1 trifluoroacetate

The 7-amino-3-phenyl- 2H-isoquinoline- 1-one obtained in Example 39 was used as a raw material, and was synthesized by a method similar to that in Example 52 and then in Example 53. h-NMR (270MHz, DMSO — d6) δ (ppm): 2.97-3.10 (5H, m), 3.64 (2H, t, J = 6.8Hz), 6.86 (1H,

s), 7.32 (lH, dd, J = 2.7, 8.9Hz), 7.35-7.53 (4H

, M), 7.62 (lH, d, J = 8.9Hz), 7.74-7.77 (2H, m), 1 1.32 (1 H, brs) ESI (LC-MS positive type) m / z294 (M + H- FTA ). [Example 5 7] 2-Chloro-N— (1-oxo-3—phenyl—1,2-monochloroisoD-quelin- 7-yl) acetamidin -112- (108) 200536830

To 200 mg (0. 0 8 5 mm ο 1) of the 7-amino-3 -phenyl- 2H-isoquinoline-1-one obtained in Example 3 9 was added 0.236 mL (1.69 mmol) of Triethylamine and 0.101 mL (1.27 mmol) of chloroacetamidine were added in this order and stirred at room temperature for 2 hours. 30 mL of 1N hydrochloric acid was added to the reaction solution, followed by extraction with dichloromethane (30 mL X 2), followed by drying over anhydrous magnesium sulfate, and then distilling off the solvent under reduced pressure. The precipitated solid was filtered and washed with an appropriate amount of ether to obtain 229 mg (86%) of 2-chloro-N- (1-oxo-3-phenyl-1,2, 2- Hydroisocyanoline 7-yl) acetamide. ^ -NMR (270MHz ^ DMSO- d6) δ (ppm): 4.3 1 (2H, s), 6.90 (ih, s), 7.38-7.52 (3H, s), 7.70 (1Η, d ' J = 8.6Hz), 7.78 (2H, m), 7.87 (lH, d, J = 2.4Hz) '8.55 (1H, d, J = 2.4Hz), 10.61 (1H, s), 1 1.49 (1 H, s) ESI (LC ~ MS positive type) m / z313 (M + H). The compounds shown below (Examples 58 to 63) were synthesized using a compound similar to that of Example 57 using the compounds obtained in Example 38 or Example 39 as raw materials. [Example 5 8] 2-Methoxy-N- (1-oxo-3-phenyl-ι, 2-dihydroiso-113- (109) 200536830 Acetylamine Kuilin- 7-yl

] H-NMR (270MHz, DMSO-d6) 5 (ppm): 3.4 1 (3H

, S), 4.06 (2H, s), 6.89 (lH, s), 7.38-7.55 (3H, m), 7.67 (lH, d, J = 8.6Hz), 7.74-7.81 (2H, m

), 7.90-7.98 (lH, m), 8.63 (lH, s), 10.08 (1H, s), 11.47 (lH, s)

El (positive) m / z 3 08 (M +). [Example 5 9] N-(1 -oxo- 3 -phenyl-1 ′ 2 -chloroisoquinine-7 -yl)-2-phenoxyacetamidamine

• 〇γ ° ^ ην iH-NMR (270 MHz, DMSO-d6) δ (ppm): 4.76 (2H, s), 6.90 (lH, s), 6.92-7.09 (3H, m) »7.28 —7.40 (2H M), 7.41—7.53 (3H, m) »7.64-7.73 (lH, s), 7.74—7.82 (2H, m), 7.90—8.00 (lH, m), 8.59 (lH, s), 10.40 (lH , S), 11.49 (lH, s)

El (positive) m / z370 (M +). -114- (110) 200536830 [Example 60]

1, 2 — • ChloroisoDquinoline 7-yl) acetamidamine

] H-NMR (270MHz, CDC13) 5 (ppm): 4), 4.69 (2H, s), 6.76 (lH, s), 7.3 7-, m), 7.46-7.55 (3H, m), 7.59-7.66 (8.17 (1H, d, J = 1.98Hz), 8.37 (1H, dd 8.58Hz), 8.60 (lH, brs), 8.98 (0.5H, br

El-MS m / z 3 84 (M +) 〇 [Example 6 1] [1-oxo-3- (2-trifluoromethylphenyl) -1 quinoline-7-yl] ethylaminoformate Ester. 1 5 (2H, s 7.42 (5.5H 3H, m),, J = 2 · 3 1, 2-dihydroiso

] Η-NMILI (270 MHz, DMSO — d6) δ (ppm), t, J = 6.8 Hz), 4.17 (2H »q, J = 6.8Hz), s), 7.60-7.87 (6Η, η〇, 8.38 (1Η, 1 H, brs), 11.50 (] H, brs) ESI (LC-MS positive) m / z377 (M + H).: 1.28 (3H, 6.41 (1H), 9.95 (-115- (111) 200536830 [Example 62]) amine (1 monooxo-3 -phenyl-1,2-dichloroisoD-quelin-7-ylethylcarboxylate)

Ο

] H-NMR (270 MHz, DMSO-d6) 5 (ppm): 1.28, t, J = 7.0Hz), 4.17 (2H, q, J = 7.0Hz), 6.86, s), 7.36-7.51 (3H, m), 7.65 (lH, d, J = i), 7.75-7.80 (3H, m), 8.38 (lH, s), 9.95 (s), l 1.43 (1 H, s)

El (positive) m / z308 (M +). [Example 63] [(1 -oxo-3-phenyl-1,2-dihydroisoD-quinolinylaminomethylamidino) methyl] aminocarbamic acid third butyl ester (3H (1H; .9Hz 1H, 7 —

W-NMRUTOMHz'DMSO— d6) 5 (ppm): 1.4 1, s), 3.77 (2H, d, J 6.2Hz), 6.88 (lH, s), —7.15 (lH, m), 7.41— 7.50 (3H, m), 7.67 (1, J = 8.9Hz), 7.72-7.80 (2H, m), 7.82-7.90

(9H 7.05 1, d (1H -116- 200536830 (112), m), 8.54 (lH, s), 10.24 (lH, s), 11.45 (1H, m)

El (positive) m / z393 (M +). [Example 64] 2-Amino-N- (1-oxo- 3-phenyl-1 '2 -_chloroisoDquinoline-7-yl) acetamido 1 trifluoroacetate

16 mg (0.0 4 1 mm ο 1) of [63 obtained in Example 6 was [(1-oxo-3-phenyl-1,2-dihydroisoquinoline-7-ylaminomethylmethyl) ) Methyl] aminocarbamic acid third butyl ester was dissolved in a mixed solvent of 1 mL of dichloromethane and 1 mL of methanol, 1 mL of trifluoroacetic acid was added, and the mixture was stirred under an ice bath for 1 hour. The solid produced by adding diethyl ether-hexane was taken out to obtain 12 mg of 2-amino-N- (1-oxo-3-phenyl-1, 2-dihydroisoquinololine-7) as a colorless solid. —Yl) Acetylamine 1 trifluoroacetate.

^ -NMR (270MHz »DMSO-d6) δ (ppm): 3.80 (2H, s), 6.90 (lH, s), 7.40-7.52 (3H, m), 7.67-7.81 (3H, m), 7.82-7.88 (lH, m), 8.14 (lH, brs), 8.53 (lH, s)

El (positive) m / z 293 (M- TFA). [Example 65] -117- (113) 200536830 2 -morpholine-4-yl-N- (1-oxo-3-phenyl-1,2-hydroisoD-quelin-7-yl) Fermented amine 〇JN Η

2-Chloro- (1-oxo-3-phenyl-1,2-dihydroisoD-quinoline-7) obtained in Example 5 7 at 50 mg (0.16 mm ο 1) To the DMF solution of acetochloramine was added 0.04 2 m L (0.4 7 mm ο 1) morpholine at 100 ° C and stirred for 30 minutes. 30 m L of 1 N sodium hydroxide was added to the reaction solution. The aqueous solution was extracted with ethyl acetate (50 ml L x 2). The extract was washed with mL of water, dried over anhydrous magnesium sulfate, and distilled off under reduced pressure. The precipitated solid was filtered with an appropriate amount of ether. Wash with hexane 'to give 44 mg (76%) of 2-morpholine-4 4-yl-1 ίν (1 -oxo-3-phenyl-1,2-dihydroisoquinoline-1) as a colorless solid. 7-yl) hydrazine.] H-NMR (270MHz, DMSO- d6) δ (ppm): 2.51 2.56 (4 Η 5 m) '3.18 (2H' s) '3.66 (4H' t 'J 4.7Hz), 6.89 (lH's), 7.38-7.52 (3H, m), 7. · (1H, d, J 2 8.6Ηζ), 7.72 — 7.80 (2H, m), 7.90 7.98 (lH, m), 8.57 (lH , D, J = 2.4Hz), 10.05 (,, s), 1 1.46 (1H, s) ESI (LC-MS positive) m / z 364 (M + H). (Example 66 and Example 67) were synthesized by a method similar to that of Example 65. N) Yuhua 30 and B 68 1 实 Η -118- (114) 200536830 [Example 66] 2-2 Methylamino-N- (1-oxo-3-phenyl-1 hydroisoquinoline-7-yl) acetamide

] H-NMR (270MHz, DMSO — d6) 5 (ppm): 2, s), 3.12 (2H, s), 6.88 (lH, s), 7.40-7, m), 7.66 (lH, d, J = 8.6 Hz), 7.76— 7.80 (), 7.92 (lH, dd, J = 2.3, 8.6 Hz), 8.62 (1H, 2.1 Hz), 10.04 (lH, s), 11.45 (lH, brs) ESI (LC- MS Positive type) m / z 322 (M + H). [Example 6 7] 30 (6H 52 (3H 2H, m d 5 J =

2- (4-methylpiperazine-1yl) -N- (1-oxoyl-1,2-dihydroisoD-quinoline-7-yl) acetamidamine 3-benzene

] H-NMR (270 MHz, DMSO-d6) δ (ppm): 1.30, 2.60 (8H, m), 3.16 (2H, s), 1H, s), 7.38-7 52 (3Η, η), 7.67 (1Η, 8.5 · ζ), 7.78 (2H, dd, J 2 1.6, 7.8Hz), 7.93 28 (3H 6.89 (d Bu J = (1H, -119- 200536830 (115), 9.99 dd, J = 2.1, 8.5Hz), 8.56 (1H, d, J = 2.1Hz) (1 H, s), 1 1.46 (1 H, brs) ESI (LC — MS positive type) m / z 377 (M + H). [Example 6 8]

6 —Morin — 4 1-Methyl 3 -Phenyl — 2 奎 —Iso-D-Querin —1 —Pay Step A

4-Chloro-2, N, N-trimethylbenzylamine was used in the same way as 3A, sd 5 J — using 4-Chloro-2 -methylbenzoic acid as the raw material, using the method of step A of Example 1 Synthetic. ] H-NMR (270MHz, CDC13) (5 (ppm): 2.27 丨), 2.83 (3H, s), 3.13 (3H, s), 7.11 (1Η, 8.1Hz), 7.1 7 — 7.23 ( 2H, m) ESI (LC-MS positive type) m / zl98 (M + H).

Step B 6 —Chloro-1, 3-Phenyl — 2 hydrazone —IsoD quelin — 1 — Wake up

Ο

CI-based benzyl was synthesized using 4-chloro-2, N, N-trimethylamidamine obtained in step A as a raw material, and was obtained by -120- (116) 200536830 in a similar manner to that in step B of Example 1. iH-NMR (270MHz, CDC13) 5 (ppm): 6.69 (lH, s), 7.42 (lH, dd, J = 1.9, 8.4Hz), 7.44-7.59 (4H, m), 7.66-7.72 (2H , M), 8.32 (lH, d, J = 8.4Hz), 9.75 (1 H, brs) ESI (LC-MS positive) m / z256 (M + H).

The 6-chloro-1,3-phenyl-1H-isoquinoline-1one obtained in step B was used as a raw material, and synthesized by a method similar to that in Example 4.

] H-NMR (270MHz, CDC13) 5 (ppm): 3.36 (4H, t, J = 5.1Hz), 3.90 (4H, t, J = 5.1Hz), 6.64 (lH, s), 6.87 (lH , D, J = 2.6Hz), 7.09 (lH, dd, J2 2.6, 8.9Hz), 7.42-7.55 (3H, m), 7.61-7.67 (2H, m), 8.27 (lH, d, J = 8.9 Hz), 8.90 (lH, brs) ESI (LC-MS positive) m / z307 (M + H). The compounds shown below (Examples 69 to 73) are based on the 7-chloro-3- (2-trifluoromethylphenyl)-2H-isoD-quinoline- 1-one obtained in Step B of Example 1 as the starting point. The raw materials were combined with -121-(117) 200536830 by a method similar to that of Example 4. [Example 69] (4aS, 8Ar) — — (2-trifluoromethylphenyl) — 3,4,4a, 5,6,7,8,8a —octahydro-1H, 2 ^ H— [2 ,] Bisisoquinolinyl-1 monoketone

iH-NMR (400MHz, CDC13) 5 (ppm): 1.02-1.05 (3H, m), 1.26-1.49 (4H, m), 1.68 (3H, m), 1.78 (2H, m), 2.47 (lH , T, J = 11.8 Hz), 2.83 (lH, dt, J = 2.8, 12.4 Hz), 3.72 (1H, d, J = 12.4 Hz), 3.91 (1 H, d, J = 1 2 · 0Ηζ), 6.44 (1H, s), 7.38 (1H, dd, J = 2.8, 8.8Hz), 7.45 (lH, t, J = 8.8Hz), 7.53 (

lH, t, J = 7.6Hz), 7.58 (lH, t, J = 7.6Hz), 7.65 (lH, t, J = 7.0Hz), 7.79-7.81 (2H, m), 8.35 (1Η, brs ) ESI (LC-MS positive) m / z 427 (M + H). [Example 70] 7- ((2S, 6R)-2,6-dimethylmorpholine-4 -yl) -3-(2 -trifluoromethylphenyl) -2H -isoquinoline -1- Ketone-122- (118) 200536830

〇

j-NMR (400MHz, CDC13) 5 (ppm):, J = 6.4Hz), 2.53 (2H, t, J = 11.4Hz) ^ J = 10.8Hz), 3.81— 3.88 (2H, m), 6 , 7.36 (1H, dd, J = 2.8 ^ 8.8Hz), 7.49 8.8Hz), 7.54 (1 H, t, J = 7.6Hz), 7.59 7.6Hz), 7.66 (1 H, t, J = 7.2Hz) , 7.78 m), 8.41 (1H, brs) ESI (LC-MS positive type) m / z403 (M + H) [Example 7 1] 7 — ((S) — 2 —hydroxymethylpyrrolidine 1 — Base) 1.30 (6H, d, 3.64 (2H, d .46 (1 H, s) (1H, d, J = (1 H, t, J = -7.82 (2H, -3 — (2 -3

W-NMR (400MHz, CDCI3) 5 (ppm) 4H, m), 2.45 (1H, brs), 3.24-3.29

3.62 (2H, t, J = 6.6Hz), 3.80 (lH, d, J 4.01 (1H, brs), 6.45 (1H, s), 7.15 (3.2, 8.8Ηζ), 7.46 (lH, d, J = 8.8Hz), 4H, m), 7.79 (lH, d, J = 7.6Hz) 8.58 (: 2.04-2.15 ((1H, m), = 1 1.2Hz), 1H, dd, J = 7.5 2- 7.65 (H 7 brs) -123- (119) 200536830 ESI (LC-MS positive type) m / z389 (M + H). [Example 72] 7-((R) -2-hydroxymethylpyrrolidine-1 1-one) -3- (2-trichloromethylphenyl)-2H-isoCIquinoline-1 1-ketone [

W-NMR (400MHz, CDC13) δ (ppm): 2.06-2.15 (4H, m), 2.50 (lH, brs), 3.24-3.29 (lH, m), 3.62 (2H, t, J = 8.8Hz ), 3.81 (lH, d, J = 10.4 Hz), 4.00 (1 H, brs), 6.45 (1H, s), 7.14 (1H, dd, J = 2, 6, 8, 8Ηζ), 7.45 (lH, d, J = 8.8Hz), 7.52— 7.65 (4H, m), 7.79 (lH, d, J = 7.6Hz), 8.61 (lH, brs) ESI (LC-MS positive type) m / z389 (M + H ) 〇 [Example 7 3] 7-Azetidine-1 1-yl-3-(2-trifluoromethylphenyl)-2H-iso-D-quinolin Blin-1 1-one

] H-NMR (400MHz, CDC13) δ (ppm): 2.43 (2Η, quintet, J = 7. · 2Ηζ), 4.0 1 (4Η, t, J = 7.4Ηz), 6.44 (-124-

200536830 (120) lH, s), 6.86 (lH, dd, J = 2.4, 8.4Hz), 7.34 (d, J = 2.4Hz), 7.43 (lH, d, J = 8.8Hz), 7.54 (, J = 6.4Hz), 7.58 (lH, d, J = 7.6Hz), 7.64 (, J = 7.0Hz), 7.80 (1H, d, J = 8.0Hz), 8.34 (brs) ESI (LC-MS positive) m / z345 (M + H). [Example 74] 4a-hydroxyl- (2-trifluoromethylphenyl) -3,4,4a ,, 7,8,8a-octahydro-1H, 2, H- [2,7,] bis Iso-r-ketone

〇 OH The 7-chloro- 3-(2-triylphenyl)-2H-isoquinoline-1 monoketone prepared in Step B of Example 1 was used as the starting material, and was synthesized by a similar method to Example 20 .

] H-NMR (400MHz, CDC13) δ (ppm): 1.30-1 lH, m), 2.15-2.22 (lH, m), 3.38 (2H, t 11.2Hz), 3.51 (2H, d, J = 11.2 Hz), 6.44 (1H, 7.35 (1H, dd, J = 2.8, 8.8 Hz), 7.45 (1H, d 8.8Hz), 7.54 (lH, t, J = 7.2Hz), 7.60 (lH, d 8.0 Hz), 7.65 (1H, d, J = 7.6Hz), 7.7 8-7.82 (m), 8. 3 1 (1 H, brs) 1H, 1 H, t 1H, t 1 H, 5, 6 phosphono .Fluorine and solid. 85 (, J =, s), J =, J = 2H,-125- 200536830 (121) ESI (LC-MS positive type) m / z443 (M + H). [Example 7 5] 1- [1 monooxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoD-quinoline-7-yl] pidinidine-4 a residual acid methyl ester

1 50 mg (0.4 63 mmol) of Example 1 prepared in Step B of 7-Chloro-3— (2-Dimethylolphenyl) —2H—Isovalin-1—one—Add 22 mg (0.056 mmol) of 2-dicyclohexylphosphino- 2〃- (N, N-dimethylamine) biphenyl, 21.1 mg (0.023 mmol) of tris (diphenylmethyleneacetone), 603 mg (1.85 mmol) ) Carbonic acid planer and dried under reduced pressure for 2 hours. Add 1 8 8 // 1 (1.39 mmol) of methyl hexahydroisonicotinate and 2.32 ml of dimethoxyethane, and stir under heating and reflux.

Stir for 17 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 17 · 5 mg (8.8%). 1- [1-oxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] piperidine-4 monocarboxylic acid . 】 H-NMR (400MHz, CDC13) (5 (ppm): 1.91-2.00 (2 Η, m), 2 · 0 1 — 2 · 1 0 (2 Η, m), 2 · 5 0-2.5 5 (1 Η, m), 2.90— 3_00 (2H, m), 3.72 (3H, s), 3.82-3.85 (-126-(122) 200536830 (122)

2 Η, m), (5.45 (1H, s) · &gt; 3.35 — -7.45 (1 Η, m), 7.48 (1H, d, J 2 8. 0Hz), 7.5 4 (1Η, d, J: 2 7 • 2Hz), 7.59 (1H, t, J = 7.6Hz), 7.65 (1Η, t, J =-Ί ', 6Hz), 7.75 —7.85 (2H 5m), 8.34 (1 ，, brs) ESI (LC-MS positive type) m / Z 43 1 (M + Η) 〇 [Example 76] 7 — (4-hydroxypiperidinyl 1 —yl) — 3 —-(L) — 1 -Yl-2H-isoquinoline-1 -one step A 7 -Chloro-3-(L) -1 -yl-2A-Isoquinone 1 -one

5-Chloro-2, N-dimethylbenzamide prepared in Step A of Example 1 was used as a starting material, and synthesized by a method similar to that in Step B of Example 1. j-NMR (270MHz, CDC13) 5 (ppm): 6.67 (1H, s), 7.50-7.70 (7H, m), 7.91-8.05 (3H, m), 8.40-8.45 (1H, m) ESI ( LC-MS positive) m / z306 (M + H).

Step B 7-(4-Hydroxypiperidine-1-yl)-3- (L) — 1-yl-2H — -127- (123) 200536830 Isoquinine-1 1-one

The 7- (4-hydroxypiperidine-1- (L) -1 1-yl-2H-isoDquinolin-1-one prepared in Step B was used as a starting point to synthesize the compound by a method similar to that in Example 20. Obtained: j-NMR (400MHz, CDC13) δ (ppm): 1.48 lH, m), 1.70-1.80 (2H, m), 2.03--2.10 (, 3.05-3.15 (2H, m), 3.75-3.85 (2H, m) 4.00 (lH, m), 6.64 (lH, s), 7.41-7.70 (, 7.93-7.96 (3H, m), 8.06 (lH, d, J 2 7. 8.49 (1 H, brs) ESI (LC — MS positive type) m / z371 (M + H). Base)-3 raw materials, borrow —1.52 (2H, m), 3.90 — 6H, m) 8Hz),

Radical)-3 7- (1,4-dioxa- 8-azaspiro [4.5] decyl-8- (2-difluoromethylphenyl)-2H-isoDquinoline- 1-one

The 7-chloro- 3-(2-ylphenyl) -2H-isoDquinoline- 1-one prepared in Step B of Example 1 was used as the starting material, and was synthesized by a method similar to that in Example 4. -128- Monotrifluoromethane, 200536830 (124)] H-NMR (2 70MHz ^ CDC13) δ (ppm): 1.86 (4H, t, J = 5.6Hz), 3.51 (4H, t, J = 5.6Hz), 4.01 (4H, s), 6.45 (lH, s), 7.38 (lH, dd, J = 2.4, 8.7Hz), 7.43-7.69 (4H, m), 7.76-7.84 (2Η , Η), 8.36 (1Η, brs) ESI (LC-MS positive type) m / z431 (M + H).

[Example 7 8] 7- (2-Hydroxymethylmorpholine-4-yl) -3- (2-trifluoromethylphenyl)-2H-isoquinoline- 1-one

HO uses 7-chloro-3- (2-trifluoromethylphenyl)-2H-isoDquinoline- 1-one prepared in step B of Example 1 as a starting material, similar to Example 20 Method. j-NMR (270MHz, CDC13) 5 (ppm): 2.2 5-2.3 8 (

lH, m), 2.77 (lH, t, J = 11.6Ηζ), 2.93 (lH, dt, J = 3.3, 11.9 Hz), 3.47-3.91 (6H, no, 4.07 (1H, dd)

, J = 2.3, 11.6Ηζ), 6.47 (lH, m), 7.37 (lH, dd, J

= 2 · 6, 8 · 9Ηζ), 7.46— 7.70 (4H, m), 7.77—7.83 (2H, s), 8.79 (1H, brs) ESI (LC— MS positive) m / z405 (M + H). -129- (125) 200536830 [Example 79]

7 — (4-monohydroxy-4—hydroxymethylpiperidine-1 mono) fluoromethylphenyl) —2H —isoquinoline-1 monoone Step A 7— (4-oxopiperidine-1— ) —3_ (2 —tri-3 — (2 -trifluoromethylphenyl) —2H —coated D quinoline —; [_one

70 mg (0.163 mmol) of Example 77, 4-dioxa-8-azaspiro [4.5] dec-8-yl) trifluoromethylphenyl)-2 hydrazone-isoD-quinoline-1 -The ketone is suspended in an equivalent amount of hydrochloric acid and stirred overnight under reflux. Add here: equivalent aqueous sodium hydroxide solution and sodium bicarbonate, ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the residue was concentrated (hexane ·· ethyl acetate = 1: 3 ~ 1: 4) to purify mg (89%) of 7- (4-oxygen) as a pale yellow solid. Phenyl group) —3— (2-trifluoromethylphenyl) —2H—isoD-H-NMR (2 70MHz, CDC13) 5 (ppm):, J = 6.2Hz), 3.75 (4H, t , J = 6.2Hz), 丨), 7.41 (lH, dd, J = 2.5,8.7Hz), 7.47-m), 7.75-7.85 (2H, m), 9.12-9.60 (i only ESI (LC-MS Positive type) m / z387 (M + H). 7 — (1 — 3 — (2 — 3 m L of 1 2.9 mL of 1) 丨 Extract the reaction solution [with a silicone tube layer to obtain 5 5.9 ED D— 1-based 1-one. 2.59 (4H, t • 48 (1H, s 7.70 (4H,, brs) -130- (126) 200536830

Step B 7— (4-hydroxy-4—hydroxymethylpiperidine—1-yl) —3— (2—trifluoromethylphenyl) —2H-isoquinoline—1—one

OH

30 mg (0.0776 mmol) of 7- (4-oxopiperidine-1-yl) -3- (2-trifluoromethylphenyl)-2H-isoquinoline-1-one, 51.3 mg (0.233 mmol) of trimethylmorpholine iodide and 26.1 mg (0.233 mmol) of sodium tributoxide were dissolved in 1.16 mL of DMS 0 and stirred overnight at room temperature. After adding water to the reaction solution, it was extracted with ethyl acetate. The extract was dried and concentrated over anhydrous sodium sulfate, and the obtained residue was purified by silica gel tube chromatography (hexane · ethyl acetate = 1: 3) to obtain 16.6 mg of a pale yellow solid. This was dissolved in 1 ml of 1,4-dioxane, and 1 ml of a 1N aqueous sodium hydroxide solution was added, followed by stirring for 2 hours under heating. Add 1 mL of 1N hydrochloric acid and saturated ammonium chloride aqueous solution, and extract with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the residue obtained after concentration was purified by silica gel column chromatography (Yijia Jiayuan. Methanol = 1 2: 1 ~ 1 0: 1) to obtain 12.2 111 g (37%) of a colorless solid. 7- (4-trifluoromethyl-4-piridylmethylpiperidine-1-yl) -3- (2-trifluoromethylphenyl)-2H-isodquinoline-1 monoone. ] H-NMR (270 MHz, DMSO — d6) δ (ppm): ι · 40—1.51 (2 Η 5 m), 1.64-1.78 (2 Η, m), 3.07—3 · 24 (4Η -131-200536830 (127), m), 3.55-3.65 (2H, m), 4.25 (lH, s), 4.60 (lH, t, J = 5.8Hz), 6.37 (lH, s), 7 · 43— 7.90 (7H, m), l 1.37 (1H, brs) ESI (LC-MS positive type) m / z419 (M + H). [Example 8 0] 3 1 (4 -methoxybenzyl)-7-Morin-4-1-2 Η-isoD quelin

Step A 5 —Chloro-2, N, N —trimethylbenzidine

〇 Using 5-chloro-2-methylbenzoic acid as a starting material, a synthesis was carried out by a method similar to that in Step A of Example 1. j-NMR (270MHz, CDC13) 5 (ppm): 2.25 (3H, s

), 2.85 (3H, s), 3.12 (3H, s), 7.15 (lH, d, J =

8.4Hz), 7.16 (lH, d, J = 2.3Hz), 7.24 (lH, dd, J = 2.3, 8.4Hz) ESI (LC-MS positive) m / zl98 (M + H).

Step B 2, N, N -trimethyl-5 -morpholine-4 -ylbenzamide -132-

I (128) 200536830

〇N, 1-H-NMR (400MHz, CDC13) synthesized by a method similar to Example 4 using 5-chloro-2, N, N-trimethylbenzidine prepared in step A as a starting material ) ό (ppm): 2.19 (3H, s), 2.84 (3H, s), 3.09— 3.13 (7H, m), 3.85 (4Η,

d, J = 4.1Hz), 6.72 (lH, d, J = 2.6Hz), 6.83 (IH, dd, J = 2.3, 8.2Hz), 7.10 (1H, d, J = 8.2Hz) ESI (LC- MS Positive type) m / z249 (M + H).

Step C 3-(4-methoxymethoxyphenyl)-1-morpholin-4-yl-2 fluorene-isoxane 1-ketone

The 2, N, N-trimethyl-5 -morpholin-4-ylbenzamide prepared in step B was used as a starting material, and synthesized by a method similar to that in step B of Example 1. ] H-NMR (400MHz, CDC13) (5 (ppm): 3 · 30 (4H, t, J: = 4.9Hz), 3.87 (3H, s), 3.90 (4H, t, J =: 4 · 9Ηζ) , 6.64 (1H, s), 7.01 (2H, d, J = 8.3Ηζ), 7.34 (1H, dd, = 2.7, 9.0 Hz), 7.49 —7.5 5 (3 Η, m), 7.78 -133- ( 129) 200536830 (lH, d, J = 2.4Hz), 8.60 (lH, brs) ESI (LC-MS positive type) m / z337 (M + H). Compounds shown below (Example 8 1 ~ 8 9) The 2, N, N-trimethyl-5-morpholine-4-yl benzamidine prepared in Step B of Example 8 was used as the starting material, and was synthesized by a method similar to the step in Example 1. Income.

[Example 8 1] 3- (2-methoxyphenyl)-7-morpholine- 4 -yl-2H-isoD-quinoline-1 monoketone

〇. iH-NMR (400MHz, CDC13) 5 (ppm): 3.31 (4H, t, J = 4.9Hz), 3.91 (4H, t, J = 4.9Hz), 3.93 (3H, s), 6.68 (lH, d, J = 2.0Hz), 7.00— 7.09 (2H, m), 7.32 — 7.58 (4H, m), 7.80 (lH, d, J = 2.9Hz) ^ 9.42 (1 H, brs) ESI (LC— MS Positive type) m / z337 (M + H). [Example 82] 3-(2 -ethylphenyl)-7-morphine-4-yl-2 fluorene-iso-D-quinolin-1-ketone -134- (130) 200536830

! Η-NMILI (400MHz, CDC13) 5 (ppm):, J = 7.8Hz), 2.71 (2H, q, J = 7.3Hz),, J = 4.9Hz), 3.91 (4H, t, J = 4.9Hz ),), 7.30-7.51 (6Η, η), 7.81 (lH, d, 1. 19 (3H, t 3.3 1 (4H, t 6.42 (1H, s 2.4Hz),

ESI (LC-MS positive type) m / z 335 (M + H) [Example 8 3] radical 1 2 H —iso 3 — (2-methylphenylmethyl) phenyl — 7 —moringine 4 1 D. Quirin 1: 1

〇0. 2.46 (3H, st, J = 4.9Hz 7.51 (1 H, 8.72 (1H,] H-NMR (400MHz ^ CDC13) (5 (ppm):), 3.30 (4H, t, J = 4.9Hz), 3.90 ( 4 Η,), 6.55 (lH, s), 7.23-7.42 (5 Η, m), d, J = 8.3Hz), 7.81 (lH, d, J = 2.4Hz), brs) ESI (LC-MS positive Type) m / z353 (M + H) &lt; [Example 8 4] -135 (131) 200536830 morpholine 1-3 — (2-bromophenyl) -7 -morpholine-4 -yl-2H -iso

ESI (LC- MS positive type) m / z385 (M + H), 3 8 7 (M + H + 2).

[Example 8 5] 2H-iso- 7-morpholine- 4 -yl- 3-(2-piperidine- 1 -ylphenyl) D

^ -NMR (400MHz ^ CDC13) (5 (ppm): 1.50 2H, m), 1.75— 1.80 (4H, m) ^ 2.90-2.94 (, 3.3 1 (4 (, t, J = 4.9Hz), 3.91 ( 4H, t, J =, 6.71 (lH, s), 7.12—7.23 (lH, m), 7.32 2H, m), 7.54 (lH, d, J = 8_3Hz), 7.61 (1) = 1.5, 7.8 Hz), 7.83 (1H, d, J = 2.4Hz), 1, brs) ESI (LC-MS positive type) m / z390 (M + H). [Example 8 6]

-1.60 (4 Η, m) 4.9Hz) -7.38 (ί, dd, J 1 .50 (1H -136- (132) 200536830 7 —Morlin 1 4 One Base 1 3-(2 —Morlin 1 4 1 Phenyl)-2H —Isoquinine-1 — Remuneration

] H-NMR (400MHz, CDC13) δ (ppm): 2.97-3.01 (4H, m), 3.30-3.33 (4H, m), 3.87-3.92 (8H, m)

, 6.69 (1 H 5 d, J = 2.0 Hz), 7.14 — 7.20 (2H, m), 7.33-7.41 (2H, m), 7.52 — 7.60 (2H, m), 7.81 (1Η, d , J = 2.4 H z), 10.9 (1H, brs) ESI (LC-MS positive type) m / z392 (M + H). [Example 8 7] 3- (2-chloro-6-methylphenyl) -7-morpholine-4 monoyl-2H-isoquinoline-1 1-one

1 85 mg (1.81 mmol) of 3.6 mL of a known epoxide in methanol solution was added to 550 mg (1.81 mmol) of 7-amino-3- (2-trifluoromethylphenyl) ) -2H-isoquinolin-1-one, and stirred at 70 ° C for 14 hours. The residue obtained by concentrating the reaction solution was purified by silica gel tube chromatography (ethyl acetate · hexane = 1: 1 to 3: 1) to obtain 3 5 6 mg (48%) of a pale yellow foamy substance. Hydroxy-3-[1-oxo-137- (133) 200536830 3-(2-trifluoromethylphenyl) -1,2-dihydroisoD-quinoline-7-ylamino] propanoic acid Methyl ester. 1H-NMR (270 MHz, DMSO — d6) δ (ppm): 3.28- 3.39 (lH, m), 3.40—3.52 (lH, m), 3.66 (3H, s), 4.26-4.34 (lH, m) , 5.78 (lH, d, J = 5.7Hz), 6 · 1 9 (1H, d, J = 6 · 2Ηζ), 7 · 1 4 (1H, dd, J = 2 · 6, 8.5Hz), 7.28 (lH, d, J = 2.4Hz), 7.41 (lH, d, J =

8.6Hz), 7.58 (lH, d, J = 7.3Hz), 7.63-7.79 (3H, m), 7.80-7.87 (lH, m), ll.27 (lH, s) ESI (LC-MS Positive type) m / z407 (M + H). [Example 8 8] 3- (3,5-dimethoxyphenyl) -7-morpholine-4-yl-2H-iso-D-quinolinone 1-one

j-NMR (400MHz, CDC13) (5 (ppm): 3.3 1 (4Η, t, J = 4.9Hz), 3.86 (6H, s), 3.91 (4H, t, J = 4.9Hz), 6.52 (lH, s), 6.70-6.75 (3H, m), 7.35 (1H, dd, J = 2.4, 8.8Hz), 7.53 (lH, d, J = 8.8Hz), 7.79 (1H, d, J = 2.0Hz) , 8.76 (1H, brs) ESI (LC — MS positive type) m / z367 (M + H). -138- (134) 200536830 [Example 8 9]

-2H 7 -morpholine-4-yl-3-(3,4,5 -trimethoxyphenyl -isoquinoline-1 -one

^ -NMR (400MHz v CDC13) 5 (ppm): 3.32 (4H, t, J = 4.8Hz), 3.91 (3H, s), 3.91 (4H, t, J = 4.8Hz), 3.95 (6H, s) , 6.66 (lH, s), 6.80 (2H, s), 7.36 (1 H, dd, J = 1.5, 8. · 3 ζ), 7 · 5 4 (1 H, d, J = 8.8 Hz) , 7.78 (lH, d, J = 2.4Hz), 8.86 (lH, brs) ESI (LC-MS positive type) m / z397 (M + H). The following compounds (Examples 90 to 96) are based on 5-chloro-2, N-dimethylbenzamide obtained in Step A of Example 1 as the starting material. Synthesized by similar methods: 0 [Example 9 0] 7 — (3 once through a cyclohexyl-1-one group) — 3 — (4-methoxyl 2 —methylphenyl) — 2 — 1 isopropyl Lin 1 woke up

-139- 200536830 (135) j-NMR (270MHz, CDC13) 5 (ppm): 1.5 8-2.0 0 (4H, m), 2.35 (3H, s), 2.48— 2.63 (lH, m), 3.13

—3 · 22 (2H, m), 3.27— 3.34 (lH, m), 3.51 (1Η, dd, J = 12.0, 3.0Hz), 3.83 (3H, s) ^ 3.93-4.02 (1 H, m ), 6.37 (lH, s), 6.78-6.82 (2H, m), 7.27 (lH, d, J = 8.0Hz), 7.37 (lH, dd, J = 8.5, 2.5Hz), 7.45 (lH, d, J = 8.5Hz), 7.81 (lH, d, J = 2.5Hz),

ESI (LC-MS positive) m / z365 (M + H). [Example 9 1] 7- (3-1-based via Kiki D)-3-(2-Morine-4-Based phenyl)-2 Η-Iso-D-Querin-1-Reward

W-NMR (270MHz, CDC13) (5 (ppm): 1.66-1.77 (2H, m), 1.83-2.01 (2H, m), 2.10 (lH, d, J = 7.0Hz), 2.96-3.00 (4H, m), 3.17—3.3 1 (3H, m), 3.5 1 (1H, dd, J-12.0 ^ 3.0Hz), 3.86—3.90 (4H, m), 3.93—4.01 (lH, m) , 6.69 (lH, d, J = 1.5Hz), 7.13-7.21 (2H, m), 7.35-7.42 (2H, m), 7.51 (lH, d, J = 9.0Hz), 7.59 (lH, dd, J) = 8.0, 1.5Hz), 7.84 (1H, d, J-2.5Hz), 10.87 (1H, brs) -140- (136) (136) 200536830 ESI (LC— MS positive) m / z406 (M + H [Example 92] 7— (3-—Based on the basic vein, 1—1 radical) —3—0—tolyl—2H—isoDquinoline—1—one

iH-NMR (270MHz, CDC13) 5 (ppm): 1.60- 1.79 (2H, m), 1.84-2.02 (2H, m), 2.25 (1H, d, J = 7.0Hz), 2.38 (3H, s ), 3.16—3.33 (3H, m) »3.50 (lH, dd, J = 12.0, 3.0Hz), 3.93-4.03 (lH, m),

6.4 1 (1H, s), 7.25— 7.40 (5H, m), 7.47 (1H, d, J -8.5Hz), 7.84 (lH, d, J = 2.5Hz), 8.48 (lH, brs) ESI (LC — MS positive) m / z 335 (M + H).

[Example 93] 7 — (3 once determined by keto-1, 1 radical) — 3 — (6 —methoxybenzopyrene, 1 2 — radical) — 2 Η —isoD

] H-NMR (500 MHz, DMSO — d6) (5 (ppm): 1.34 —

1.41 (] H, m), 1.50—1.57 (lH, m) ,: 1.7 7—1.81 (1H -141-(137) 200536830, m), 1.90 — 1.94 (ιη, ιώ), 2.74 2.78 (lH, m), 2.88—2.39 (1Η, η), 3.17 (lH, d, J = 3.0Hz) &gt; 3.60-3.70 (2Η, m), 3 · 7 8 (1 Η, dd, J (2.65, 3.0Hz), 3.78 (3H, s), 7.16 (lH, dd, J = 9.0, 3.0Hz) &gt; 7.32 (1H, brs), 7.48 (1 H, dd, J = 8.5, 3.0Hz), 7.56 (lH, d, J = 3.0Hz), 7.73 (lH, d, J = 8.5Hz), 7.75 (lH, d, J = 3.00Ηζ), 7.94 (lH, d) , J = 9.0Hz)

ESI (LC-MS positive) m / z408 (M + H). [Example 9 4] 7- (3-hydroxypiperidine ~ 1-yl) -3- (2-morpholine-4-ylmethylphenyl) -2H-isoquine Blin-1 monoketone The 2-morpholine-4-methylmethylbenzonitrile in the coupling reaction is based on methods known in the literature (for example, the preparation of Bu 11 etinde 1 'A cademie Polonaise des Sciences, serie des Sciences Chimiques (1972), 20 (5) , 405-9, or WO 2003/048164, etc.), modulated by cyanobenzyl bromide and morpholine.

j-NMR (270MHz, CDC13) 6 (ppm): 1.62-1.74 (2H, m), 1.82-2.00 (2H, m), 2.07- 2.17 (lH, m), 2.61- 2.71 (4H , M), 3.15-3.31 (3H, m), 3.48 (lH, dd, J = 12.0, 3.0Hz), 3.51 (2H, s), 3.90-4.00-142-200536830 (138) (5H, m), 6.59 (lH, s), 7.25— 7.47 (4H, m), 7.51 (1 H, d, J = 9.0 Hz), 7 · 6 8 (1 H, dd, J 2 7.5, 1 · 5Ηζ), 7 · 83 (1H, d, J = 2.5Hz), 13.25 (1H, brs) ESI (LC-MS positive type) m / z420 (M + H). [Example 9 5] 7- (4-hydroxypiperidine-1 1-yl)-3-[2- (methylphenylamino

) Phenyl]-2 Η 1

] H-NMR (400MHz, CDC13) 5 (ppm): 1.50 (1H, m), 1.65 — 1.73 (2H, m), 2.00 — 2.05 (2H, m) ^ 3.01 — 3.09 (2H, m), 3.11 ( 3H, s), 3.68-3.74 (2H, m), 3.85-3.95 (lH, m), 6.57 (lH, s), 6.78-6.82

(3H, m), 7.16-7.25 (2H, m), 7.27-7.45 (5H, m), 7.61 (lH, d, J = 7.1Hz), 7.75 (lH, s), 9.21 (1 H, brs) ESI (LC— MS positive) m / z426 (M + H). [Example 96] 3- (4-fluoro-2-trifluoromethylphenyl) -7- (4-hydroxypiperidine-1 1-yl) -2H-isoDquinolin-1-one-143-200536830 (139)

j-NMR (400MHz, CDC13) 5 (ppm): 1.40 lH, m), 1.68 — 1.76 (2H, m), 2.02-2.09 (, 3.04 — 3.17 (2H, m), 3.70-3.79 (2H, m) 3.98 (lH, m), 6.42 (lH, s), 7.27-7.40 (, 7.43-7.57 (3H, m), 7.81 (lH, s), 8.3 brs) ESI (LC-MS positive) m / z407 (M + H). [Example 97] 7- (4-hydroxypiperidine-1-yl) -3- (2-morpholine-4

) —2 Η —Iso-D-Querin-1 — 嗣 Step A 7 -Chloro-3— (2-morpholine-4-ylphenyl) —2H —Iso-D-Quinone—1.50 (2H, m), 3.87- 2 Η, m) 1 (1H, -ylphenylline-1-

5.39 mL (9.69 mmol) of 1.8M lithium diisopropylhydrazone liquid was diluted with 68 mL of THF, and here 78T: dripped 3 5 3 mg (1.94 mmol) prepared in Example 80 Step A A solution of 2, N, N-trimethylbenzamide in THF. In this g of THF, 5 mL of 5-chloro was added to 5-144- (140) 200536830 ml of 4 3 8 mg (2.3 3 mm ο 1) of THF in 2 mL of THF. The solution was stirred at -7 ° C for 30 minutes. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oil which was crystallized with hexane / ethyl acetate (3: 1). The resulting solid was filtered to obtain 5 7 5 mg (87%) of colorless crystals of 7-chloro-3- (2-trifluoromethylphenyl) -2H-isoD-quinoline-1-one.

j-NMR (400MHz, CDC13) 5 (ppm): 2.97-3.00 (4H, m), 3.87-3.90 (4H, m), 6.71 (1H, s) »7.19 (2H, m), 7.43 (1H» dt , J = 1.2, 7.6 Hz), 7.53 (1H, d'J = 8.4 Hz), 7.59 — 7.62 (2H, m), 8.39 (1H js), 1 1 · 10 (1 H, brs) ESI (LC —MS positive type) m / z341 (M + H).

Step B

7- (4-one via hydrazone-1—one group) —3 -— (2-morpholine—4-ylphenyl) —2H—isoD-quinoline—1—one

7—Chloro-3— (2-morpholine—4-phenylphenyl) —2H—isoD | line— obtained in step A; [—one as the starting material was synthesized by a method similar to that in Example 20. . 】 H-NMR (400MHz, C D C13) δ (ppm): 1.48 (1H, d -145- (141) 200536830

, J = 4.4Hz), 1.70-1.77 (2H, m), 2.03-2.07 (2H, m), 2.96- 3.02 (4H, m), 3.04-3.13 (2H, m), 3.71- 3.78 (2H, m), 3.86-3.94 (5H, m), 6.67 (1Η, s), 7.12-7.21 (2H, m), 7.32-7.42 (2H, m), 7.50 (1 H, d, J = 8 · 8Ηζ), 7 · 5 8 (1 H, dd, J 2 1.4, 8.0 Hz), 7.82 (1H, d, J = 3.2 Hz), 10.84 (1H, brs) ESI (LC-MS positive Type) m / z406 (M + H).

The compounds shown below (Example 9 8 to 1 0 1) and Example 8 0 5-Chloro-2, N, N-trimethylbenzamide prepared in step A were used as starting materials. 97 Synthesized by similar methods. [Example 9 8] 3-bisphenyl-2-yl-7- (3-hydroxypiperidine-1-yl) -2H-isoDquinolinone 1-one

j-NMR (270MHz, CDC13) δ (ppm): i.5 7-1.7 6 (2H, m), 1.82—1.99 (2H, m), 2.12—2.22 (lH, m), 3.11— 3.29 (3H, m), 3.46 (lH, dd, J = 12.0, 3.0Hz), 3.90-4.00 (lH, m), 6.42 (lH, s), 7.28 -7.57 (llH, m), 7.72 (lH , D, J = 2.5Hz), 8.07 (1 H, brs) ESI (LC-MS positive type) ni / z397 (M + H). -146- (142) 200536830 [Example 99] 2H, t 2H I = 2.0 5 • 85 Oxybenzene 3- (2-ethylphenyl)-7- (3-Based on D-A-1) Iso-isoquinoline-one

j-NMR (270MHz, CDC13) (5 (ppm): 1.18 (3H, J = 7.5Hz), 1.65-1.79 (2H, m), 1.84-2.00 (, m), 2.15 (lH, d, J = 7.0Hz), 2.71 (2H, q, · 7.5Hz), 3.16—3.3 (3H, m), 3.49 (lH, dd, J = l ^ 3.0Hz), 3.94—4.03 (1 H, m), 6.40 (1H, s) 7.24— 7.43 (5H, m), 7.47 (lH, d, J = 8.5Hz), 7 (lH, d, J = 2.5Hz), 8.31 (lH, brs) ESI (LC-MS Positive type) m / z349 (M + H). [Example 100] 7- (4-hydroxypiperidine-1-yl) -3- [2- (2-methoxyethyl) phenyl]-2H -IsoD-Querin—1—Also, 2- (2-methoxyethoxy) carbonitrile used in the coupling reaction is known from literature (for example, WO 2003/04 8 1 64, etc.) from cyanobenzene Prepared with methyl bromide and morpholine. -147- (143) 200536830

i H-NMR (270MHz, CDC13) δ (ppm): 1.7 3-1.7 8 (2H, m), 2.01-2.08 (2H, m), 3.01-3.11 (2H, m), 3.57 (3H, s), 3.71— 3.77 (2H, m), 3.79— 3.82 (2H, m), 3.85— 3.93 (lH, m), 4.28— 4.32 (2H, m)

, 6.65 (lH, s), 6.99— 7.10 (2H, m) ^ 7.3 1-7.40 (

2H, m), 7.49 (lH, d, J = 8.58Hz), 7.55-7.59 (1H, m), 7.83 (lH, d, J = 2.64Hz), 10.1 (lH, brs) ESI (LC-MS positive Type) m / z 395 (M + H). [Example 1 〇1] 4- {2- [7- (3-hydroxypiperidine-1 1-yl) -1 1-oxo-1,2-dihydroisoquinoline-3-yl] phenyl} Piperazine-1—the third butyl carboxylic acid and 2- (4-tert-butoxycarbonyl) used in the coupling reaction. Piperazine-1-ylbenzonitrile is known in the literature (for example, WO 20 03). / 04 8 1 64, etc.), prepared from cyanobenzyl bromide and morpholine 0-148- (144) 200536830

〇 / Ο

] H-NMR (2 70MHz, CDC13) 5 (ppm): 1.44), 1.60-1.78 (2H, m), 1.86-2.01 (2H, m -2.34 (lH, m)), 2.87— 2.98 (4H, m ) ^ 3.14 3H, m), 3.52 (1H, dd, J = 12.0, 3.0 Ηζ) 3.64 (4H, m), 3.91—4.01 (lH, m), 6.68 (, 7.11 (lH, d, J = 8.0Hz), 7.17 (lH, t, J =, 7.34—7.40 (2H, m), 7.50 (lH, d, J = 9. 7.58 (1H, dd, J = 8.0, 1.5Hz), 7.83 (1H, 2.5Hz), 10.84 (1H, brs) ESI (LC-MS positive type) m / z 505 (M + H) 〇 (9H, s), 2.24 -3.35 (, 3.55— 1 Η, s) 8.0Hz) 0 Η z), d, J =

[Example 102] Phenylphenyl 7- (3-hydroxypiperidine- 1-yl) -3-(2-piperazine-1) -2

1 1 · 5 mg (0.0 2 2 7 mm ο 1) of Example 1 0 1 {2— [7-(3-via piperidine D 1-1 -yl)-1-oxo; get 4 — 6 — 1,2-149- (145) 200536830 Dihydroisoquinoline-3-yl] phenyl 丨 piperazine-1 1 Dibutyl chloride solution of a third butyl residual acid (0.311L) Diacetic acid (0.2 m L) was added to the sample at room temperature. The residue obtained by desolvating the solvent under reduced pressure was purified with β ο nd ElutNH2 (registered trademark Balian, lg, dichloromethane: methanol = 2 0 ·· 1) to obtain 8.9 mg (97%) of a yellow solid. 7- (3-1-yl via a base vein D) -3- (2-Axyl-1 -ylphenyl) -2H-isoI] quinoline- 1-one.

] H-NMR (270MHz, CDC13) δ (ppm): 1.64-2.02 (5H, m), 2.95-2.99 (4H, m), 3.05-3.08 (4H, m), 3.15-3.34 (3H, m), 3 · 5 1 (1 H, dd, J = 12 · 0, 3.0 Hz), 3.94 — 4.01 (1H, m), 6.69 (1H, d, J = 1.5 Hz), 7.13-7.18 (2H, m), 7.34 — 7.40 (2H, m), 7.51 (lH, d, J = 8.5Hz), 7.59 (lH, dd, J = 8.〇, 1.5Hz), 7.84 (1H, d, J = 2.5Hz), 11.18 (1H, brs) ESI (LC-MS positive type) m / z405 (M + H). [Example 103] 7- (3-hydroxypiperidine-1 1-yl) -1 3- [2- (4-methylpiperazine-1 1-yl) phenyl] -2H-isoquinoline-1-one

In 3.6 mg (0 · 0 0 8 9 mm ο 1) obtained in Example 1 〇2: (3-via base warming-1-1 base)-3-(2-Qixiao-1- Phenyl-150- (146) (146)

200536830 A 2H-isoD-quinolinone-1-one acetonitrile solution (0.4 mL) 0.0185 mL (0.133 mmol) of triethylamine and 0.00665 mL mmol) of methyl iodide, and stirred at room temperature for 4 hours. Distilled under reduced pressure, and the obtained residue was purified by thin-layer chromatography (NH2, F254s, Mellow developing solvent; dichloromethane: methanol = 1 0: 1, Rf 値: 0.8) to obtain 1.8 mg (48%) of Yellow solid 7-ylpiperidine- 1-yl) -3— [2- (4-methylpiperazine-1 1-yl] -2 Η-Isovalin-1—Payment.] H-NMR (270MHz , CD3OD) 5 (ppm): 1.4 1 (lH, m), 1.64-1.77 (1Η, π), 1.90-2.07 (), 2.38 (3H, s), 2.48— 2.66 (4H, m), 2.83 dd, J = 12.0, 8.0 Hz), 2 · 9 0-3 · 0 3 (5 H, m), 3.64 (lH, m), 3.73-3.87 (2H, m), 6.87 ( 1:, 7.17 (1H, ddd, J = 8.0, 8.0, 1.5Hz), 7.22 (, J = 8.0, 1.5Hz), 7.40 (1H, ddd, J = 8.0, 1.5Hz), 7.50 ( 1H, dd, J = 9.0, 3.0Hz), 7.58 dd, J = 8.0, 1.5Hz) 7.63 (1H, d, J = 9.0Hz), 1H, d, J = 3.0Hz) ESI (LC — MS positive M / z419 (M + H). [Example 104] 7-thiomorpholine-4, 4-yl-1, 3- (2-trifluoromethylphenyl) iso-D-quinoline-1, 1-ketone was added by mouth (0.107 to a solvent company, and exhibition (3 -Hydroxy) benzene — 1.55 2H, m (1H, 3.56 — Η, s) 1Η, dd 8.0 ^ (1H, 7.71 (2H--151-(147) 200536830

The 7-chloro-3-(2 -digas-_implementation base)-2H-isoquinololine-obtained in Step B of Example 1; -Ketone was used as a starting material, and was synthesized by a method similar to that of Example 4. 1 2 85 (H-NMR (270MHz, CDC13) 5 (ppm): 2.7.0

7.32 4H, m), 3.65—3.83 (4H, m), 6.46 (1H, S) 'm), (1 H, dd, J 2 2.6, 8.9Hz), 7.4 5 — 7 · 7 0 (4 Η' 7.75 (1H, d, J = 2.6Hz), 7.81 (1H, d, J2 7.3ίί) 8.93 (1H, brs) ESI (LC — MS positive) m / z391 (M + H). [Example 1 05]

7-(1 -oxothiothiomorpholine-4 -yl)-3-(2 -diP phenyl)-2H-isoquinoline-1 -one

2 0.1 mg (0.05 15 mmol) of the thiomorpholine 4-diyl-3- (2-trifluoromethylphenyl) -2H-isoxoline ~ 1 monoketone obtained in Example 104 was dissolved in 2.3 mL of dichloromethane was added thereto, and 9.8 mg (0.055 m in ο 1) of m-chloroperbenzoic acid was added thereto, and the mixture was stirred at 0 ° C for 2 hours. Saturated aqueous sodium bicarbonate solution was added for extraction with dichloromethane, and the -152- (148) 200536830 solution was dried with anhydrous sodium sulfate, and the resulting residue was concentrated by chopping the tube for chromatography (chloroform: methanol = 2 0: 1 ) Purified to obtain 16 · 6 ni g (79%) of 7-(1-oxothiomorpholine-4 -yl) _ 3-(2-trifluoromethylphenyl) as a pale yellow solid. A 2H-isod quinoline one; i a ketone. 1H-NMR (270MHz 'CDC13) § (ppm): 2.8 0-3.00 (4H, m), 3.80 (2H, dt, J = 14.9, 3.8Hz), 4.16 (2Η, ddd, J = 3.8, 9.2 , 13.9 Hz), 6.47 (1H, s), 7.37 (

1H 'dd, J = 2.6, 8.9Hz), 7.50-7.70 (4H »m), 7.77 —7.85 (2H, m), 8 · 8 1 (1 H, brs) ESI (LC — MS positive) m / z407 (M + H). The following compounds (Examples 106 to 107) were prepared using 7-chloro-3 (2-trifluoromethylphenyl) -2H-isoquinoline-1 monoketone obtained in step B of Example 1 The starting materials were synthesized by a method similar to that of Example 20. [Example 106] 7-((R) -3-Hydroxypiperidine-1-yl) -3- (2-trifluoromethylphenyl)-2H-isodanolin-1-one

] H-NMR (270 MHz, CDC13) 5 (ppm): 1.5 8-1.8 0 (2H, m), 1.82-2.00 (2H, m), 2.18 (lH, d, J = 6.9Hz), 3.13- 3.38 (3H, m), 3.51 (lH, dd, J = 3.0 • 153- 200536830 (149), 12.2Hz), 3.91—4.02 (1H, m), 6.45 7.39 (1H, dd, J- (2.3 ^ 8.9Hz), 7.43-7., 7.77— 7.86 (2H, m), 8.50 (lH, brs) ESI (LC-MS positive type) m / z 389 (M + H) [Example 1 〇7] 7 — ((S) a 3-determined by Kiqi — 1 a base) — 3-

(1H, s), 7 0 (4 Η, m) 2 -trifluoromethylphenyl)-2 Η-iso-P 咐 1-

W-NMR (270MHz, CDC13) δ (ppm): 2H, m) ^ 1.82-2.03 (2H ^ m), 2.32 (

6 · 6 Hz), 3.13—3.38 (3H, m) ^ 3.52 (1H, 12.0Hz), 3.91—4.02 (1H, m), 6.45 7.38 (1H, dd, J = 2.6 ^ 8.9Hz), 7.44-7., 7.77 — 7.85 (2H, m), 8.69 (lH, brs) ESI (LC-MS positive type) m / z389 (M + H). The following compounds (Examples 108 to 1 1 1) were synthesized from 2, N, N-trimethyl-5-morpholine monoamine obtained in Step B as the starting material, and were synthesized by the same procedure as in Step B of Example 1. Income. [Example 1 〇8] 1.60-1.8 0 (1 Η, d, J =, dd, J = 3.1 (1 H, s), 70 (4H, m) Example 80 Step 4 Monomethyl benzamidine -154- (150) 200536830 7 —Moryl — 4 —Methyl — 3 — O —Tolyl — 2H —Iso D Quilin — 1 — Reward

〇0. ] H-NMR (400MHz, CDC13) δ (ppm): 2.4 1 (3Η, s), 3.30 (4H, t, J = 4.9Hz), 3.91 (4H, t, J = 4.9Hz), 6.42 (1H, s), 7.28— 7.37 (5H, m), 7.50 (1H,

d, J = 8.8Hz), 7.81 (lH, d, J = 2.9Hz), 8.37 (1H, brs) ESI (LC-MS positive type) m / z321 (M + H). [Example 109] 7-Moryl-1 4-Methyl-1 3-(L)-2 -Methyl-2 2 hydrazine-Isoquinone Olin-1 1-one

Ο 1H-NMR (400MHz, CDC13) δ (ppm): 3.33 (4Η, t, J = 4.9Hz), 3.91 (4H, t, J = 4.9Hz), 6.87 (lH, s), 7.37 ( lH, dd, J = 2.4, 8.8Hz), 7.50-7.60 (3H,

m), 7.74 (lH, dd, J = 1.7, 8.5Hz), 7.82 (lH, d, J -2.9Hz), 7.85-7.93 (2H, m), 7.96 (lH, d, J = 8.8 Hz) , 8.06 (1H, s), 8.80 (1H, brs) ESI (LC-MS positive type) m / z357 (M + H). -155- (151) 200536830 [Example 1 1 0] 3-(2-monomethylaminophenyl) -7-morpholin-1 4-yl-1 2H-isopropylquinone 11-1

〇0.

The 2- (N, N-dimethylamino) benzonitrile used for the reaction is prepared by a method known in the literature (for example, J. Org. Chem., Vol. 48, No. 293 3-2935 (1983), etc.) . ^ NMRMOOMHz ^ DCh) 5 (ppm): 2.71 (6H, s), 3.31 (4H, t, J = 4.8Hz), 3.91 (4H, t, J = 4.8Hz), 6.70 (lH, s), 7.09- 7.25 (2H, m), 7.33-7.37 (2H, m), 7.52-7.57 (2H, m), 7.81 (lH, s), 10.70 (1 H, brs) ESI (LC-MS positive) m / z350 (M + H). [Example 1 1 1] 7 —Moryl-4 —yl — 3 — (2-pyrrolidine-1 —ylphenyl) — 2H — isoDquinoline 1 —one

〇 ^ 2- (1-pyrrolidinyl) benzonitrile used in the reaction is described in the literature -156- (152) (152)

200536830 well-known method (for example, US 2002/0193389, etc.)] H-NMR (400MHz, CDC13) 5 (ppm 4H, m), 3.04-3.08 (4H, m), 3.4.8Hz), 3.90 (4H, t, J = 4.8Hz),

6.96 — 7.02 (2H, m), 7.31—7.53 (4H, s), 9.67 (1 H, brs)

ESI (LC — MS positive type) m / z 376 (M + H [Example 1 1 2] 7-((S)-2,3-dihydroxypropylamino) phenyl) -2H-isoD Quinoline-l-one is prepared. ): 1.8 5-1.9 0 (30 (4H, t, J = 6.61 (1H, s),, m), 7.80 (1H) °-3— (2-trifluoromethyl

To a solution of 608.5 mg (2.0 based 3- (2-trifluoromethylphenyl) -2H-isoalcohol (10 mL) obtained in Example 38) was added 132.6 mL (20 r sugar alcohol), and the mixture was stirred under reflux overnight. Concentration reaction: Silica gel column chromatography (dichloromethane: methanol = 20: to 5 1 4.3 mg (68%) of light yellow amorphous 3-dihydroxypropylamino group)-3-(2-3 Flumisoquinoline-1 monoone. 1H-NMR (270 MHz, DMSO — d6) δ 3.05 (lH, m), 3.23—3.46 (3H, m)

mmol) of 7-aminoquinoline-1 monoketone in ethyl nmol) (R) after 1 man is purified by 1) to obtain 7 — ((S) -2, ylphenyl) — 2H — ( ppm): 2.95-, 3.64-3.73 (1H -157- (153) (153)

200536830, m), 4.66 (lH, t, J = 5.3Hz), 4.84 (1Η 5.0Hz), 6.03 (lH, t, J = 5.4Hz), 6.29 (1

7.13 (1 H, dd, J = 2.0, 8.8 Hz), 7.24 (1 H

2.0Hz), 7.40 (lH, d, J = 8.8Hz), 7.58 (1H 7.5Hz), 7.66 (lH, d, J = 7.5Hz) ^ 7.75 (11 7.5Hz), 7.84 (lH, d, J = 7.5Hz) »1 1 .24 (It ESI (LC-MS positive type) m / z 379 (M + H). [Example 1 1 3] 7 — ((R) — 2, 3 —dihydroxypropyl Amine) -3- (2-ylphenyl) -2H-isoquinoline-1 monoketone

HO was used in the synthesis of 7-amino- 3-(2-ylphenyl)-2H-isoquinoline- 1-one obtained in Example 3 8 in the same manner as in Example 12. 1 H-NMR (270MHz, DMSO-d6) δ (ppm) 3.05 (lH, m), 3.20—3.46 (3H, m), 3.64—, m), 4.60— 4.70 (lH, m), 4.85 ( lH, d,), 6.00—6.08 (lH, m), 6.29 (lH, s), 7.dd, J = 2.0, 8.3Hz), 7.24 (lH, s), 7.40 (-8.3Hz), 7.58 ( lH, d, J = 7.3Hz), 7.66 (-7.3Hz), 7.75 (lH, t, J = 7.3Hz), 7.84 (H, s), d, J = [, d, J = I, t , J = I, brs) — trifluoromethyl

A trifluoromethane-like formula: 2.95 — 3.73 (1H J = 4 · 6Ηζ 13 (1H, 1H, d, J 1 Η, t, J 1H, d, J -158- (154) 200536830 = 7.3Hz), 1 1.24 (1 Η, brs) ESI (LC-MS positive type) m / z379 (M + H). [Example 1 M]

7-imidazole- 1-yl-3 3 ((2-trifluoromethylphenyl) _2H-isoquinine-1 1 pay step A

7-Keto-3- (2-Difluoromethylphenyl)-2H-isoD-quinoline- 1-one

1.52 g (5.0 mmol) of 7-amino-3- (2-trifluoromethylphenyl)-2H-isoquinololine- 1 -one obtained in Example 38 was dissolved in acetic acid

1 mL of aqueous sulfuric acid (30 mL) and 862.5 mg (12.5 mmol) of sodium nitrite were added to the solution (15 mL) at 0 ° C. After stirring for 30 minutes, 2.62 g (17.5 mmol) of sodium iodide, 952.3 mg (5.0 mmol) of copper (I) iodide was stirred at 80 ° C. for 1 hour. After the reaction solution was cooled, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the residue obtained after concentration was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 4 ~ 1: 2) and washed with sodium thiosulfate aqueous solution. After that, 1.87 g (90%) of 7-fluorene: -3- (2-trioxomethylphenyl) -2H-isoD-quinolin-l-one was obtained as a pale yellow solid. ] H ^ NMR (270MHz »CDC13) 5 (ppm): 6.47 (1H, s -159- (155) 200536830), 7.31 (lH, d, J = 8.6Hz), 7.55 (lH, dd, J = 1.7, 7.3 Hz), 7.59-7.73 (2H, m), 7.83 (1H, dd, J = 2.0

, 6.9 Hz), 7 · 9 6 (1 H, dd, J = 1 · 8, 8 · 4 H z) 5 8.72 (1 H, d, J = 1.6 Hz), 9.06 (1 H, brs) ESI (LC-MS positive type) m / z416 (M + H).

Step B

7-imidazole-1, 1-yl-3, (2-trifluoromethylphenyl) -2H-isoquinoline-1 monoone

0

The 10.4 mg (0.025 mmol) of 7-iodine-3 (2-difluoromethylphenyl) -2H-isoD obtained in step A was prepared from 1-ketone, copper (I) iodide 0.48 mg (0.0025 mmol), 2.0 mg (0.03 mmol) of miwa, and 11.1 mg of potassium phosphate were suspended in 0.25 5 L of 1,4-dioxin, and 2.6 // L of N, N / —Dimethylethylene diamine, stirred overnight at 110 ° C. After the reaction solution was cooled to room temperature, a saturated ammonium chloride aqueous solution was added to the reaction solution, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the residue obtained after concentration was purified by silica gel column chromatography (dichloromethane: methanol 25: 1 to 20: 1) to obtain 8.3 mg (93%) of a colorless viscous oily substance. 7-imidazole- 1-yl- 3-(2-trifluoromethylphenyl)-2H-isoquinoline- 1-one. H-NMR (270MHz, CDC13) (5 (ppm): 6.58 (1H, s-160- (156) 200536830), 7.24 (lH, s), 7.41 (lH, s), 7.55-7.77 (5Η, m), 7.84 (1H, dd, J = 1.7, 7 · 6Ηζ), 7.98 (1H, s), 8.35 (lH, d, J = 2.0Hz), 9.89 (lH, brs) ESI ( LC-MS positive type) m / z 356 (M + H). [Example Π 5] 7- [1,2,4] triazole-1 1-yl 3- (2-trifluoromethylphenyl)

1 2 Η — 异 D 琳琳 —1 嗣

The 7-iodo-3-(2-trifluoromethylphenyl) -2H-isoquinoline-1 monoone obtained in step A was used as the starting material, and was synthesized in a similar manner to that in step B of Example 1 4 Income. iH-NMR (2 70MHz, CDC13) δ (ppm): 6.58 (1 (, s

), 7.55— 7.75 (4H, m), 7.80— 7.88 (lH, m), 8.16 (lH, s), 8.17 (lH, dd, J = 2.3H, 8.6Hz), 8.64 ( lH, d, J = 2.3Hz), 8.68 (lH, brs), 8.75 (lH, s) ESI (LC-MS positive) m / z 357 (M + H). [Example 1 1 6] 7-tetrazol-1-yl-3- (2-trifluoromethylphenyl) -2H-isodquinoline-1 1-one -161-(157) 200536830

The 7-amino- 3 -yl) -2H-isoquinolin-1-one in acetic acid solution C 17.5 // L (0.16 mmol) trimethyl orthoformate jmm ο 1) obtained in Example 38 After stirring the sodium nitride at 80 ° C for 6 hours to room temperature, water was added and the mixture was extracted with ethyl acetate. After the extracted sodium aqueous solution was washed, the residue was dried over anhydrous sodium sulfate and subjected to silica gel column chromatography (ethyl acetate: hexane =, to obtain 29.8 mg (83%) of 7 3 — (2-trifluoromethyl) as a colorless solid. Phenyl) -2H-isoxolinoline-W-NMR (270MHz, CDC13) δ (ppm:), 7.57-7.90 (5Η, m), 8.19 (1Η 8.6Hz), 8.61 (lH, d, J = 2.3Hz), 9 9 · 7 1 (1 Η, brs) ESI (LC— MS positive type) m / z 358 (M + H: [Example 1 1 7] 7— ((R) — 3-benzyloxy-2-methylamine 3 (2-trifluoromethylphenyl)-2H-isoquinoline-1 1 [Example 1 1 8] 7- ((R) -4-benzyl To oxymethyl- 3 -methyl (2-trifluoromethylbenzene. 2 ml, add S 9.8 mg (0.15 hours. The reaction solution cooling solution is saturated hydrogen carbonate, concentrated 2: 2) and purified- Tetrazol-1 1-yl-1 -one.: 6.26 (1H, s, dd, J = 2 · 3, • 24 (1H, s), o Bpropylamino-1-3-keto ^ imidazolidine-1 1- -162- (158) 200536830) 3- (2-trifluoromethylphenyl)-2H-isoquinoline-1-one

Chiral

Chiral

Fmoc-Meser (Bzl) — OH at 1 g (2.3 mmol)

In a solution of methyl chloride, add 1.2 g (2.8 mmol) of BOP solution, 0.5 mL (3 mmol) of N, N-diisopropylethylamine, and 273 mg (2.8 mmol) of N, 0-di Methylhydroxylamine hydrochloride was stirred at room temperature overnight. The reaction solution was washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution in that order, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2). Of the 850 mg of the obtained oil, 238 mg was used as a 2 mL THF solution, and 8 niL of a 10 mg (0.25 mmol) lithium aluminum hydride solution in THF was added dropwise at -78 ° C. After stirring at -78 ° C for 1.5 hours, 10 mg (0.2 5 mm ο 1) of lithium hydride was added, and the mixture was stirred at 78 ° C for 30 minutes. The reaction solution was added with a saturated ammonium chloride aqueous solution at -78 ° C, and after warming to room temperature, it was filtered through celite, and the filtrate was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the resulting oil was concentrated under reduced pressure. The oil was dissolved in 5 mL of methanol without purification, and 100 mg (0.33 mmol) of 7-amine group was added by mouth. -3-(2-trifluoromethylphenyl)-2H-isoquinoline-1 -one, 1 mL of acetic acid. Add 135 mg (2.1 mmol) of sodium cyanotrihydroborate under ice bath and warm to room temperature -163- (159) 200536830

After stirring for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane, and the extract was dried and concentrated with anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexanedi 1: 2 ~ 2: 1) to obtain a yellow foam. 1 mL of piperidine was added to 5 mL of the dichloromethane-complete solution of the yellow foaming substance, and the mixture was stirred at room temperature. After 4 hours, the reaction solution was concentrated, 2 mL of 1N hydrochloric acid and 2 mL of methanol were added, and the mixture was stirred at 40 ° C. After 6 hours, the reaction solution was neutralized with a 1N sodium hydroxide aqueous solution under cooling, and a saturated sodium bicarbonate aqueous solution was added thereto, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by amine TLC (Fuji Silesia Chemical Co., Ltd. PLC05: dichloromethane: methanol = 20: 1) to obtain 48 mg (31%) of 7-((R)- At the same time as 3-benzyloxy-2-methylaminopropylamino-3- (2-trifluoromethylphenyl) -2H-isoquinoline-1-one, 2 8 mg (1 7%) of 7-((R) -4benzyloxymethyl-3-methylimidazolidine-1yl) as a yellow foamy substance—3- (2-trifluoromethylphenyl) -2H-isoD-quinoline- 1-one. 7- ((R)-3 -benzyloxy-2-methylaminopropylamino-3-(2-trifluoromethylphenyl)- 2H-isoDquinoline-1 monoone [Example 117]] H-NMR (270MHz »CDC13) (5 (ppm): 2.43 (3H, s), 2.99-3.04 (lH, m), 3.18-3.27 ( lH, m) ^ 3.34-3.42 (lH, m), 3.54-3.66 (2H, m), 4.55 (2H, s

), 4.73 (lH, brt), 6.42 (lH, s), 7.01 (lH, dd, J -164- (160) (160)

200536830 = 2.31, 8.24Hz), 7.31— 7.39 (6H, m), 7 ^ J = 2.47Hz), 7.52— 7.67 (3H, m), 7.80 = 6.76Hz) ESI (LC—MS positive) m / z482 (M + H). 7— ((R) — 4 —benzyloxymethyl — 3 —methylimidazolium) — 3 — (2-trifluoromethylphenyl) — 2H —isoquinoline-Example 1 1 8]] H-NMR (270MHz ^ CDC13) δ (ppm): 2), 3.05-3.10 (lH, m), 3.38-3.44 (1H, (lH, dd, J = 5.44, 9.73Hz), 3.63-3.71 (

3.86 (lH, d, J = 4.78Hz), 4.57 (lH, d, J, 4.60 (2H, s), 6.44 (lH, s) ^ 6.91-6.

), 7.27 — 7.3 7 (5H, m), 7,43 (1H, d, J, 7.47 — 7.67 (3H, m), 7.80 (lH, d, J = 8.30 (1H, s) ESI (LC— MS Positive type) m / z494 (M + H). [Example 1 1 9]

7-methylamino-3- (2-trifluoromethylphenyl)-2H

1-one step A 7-bromo- 3- (2-trifluoromethylphenyl) -2H-isoamidine

.48 (1 Η, d (1H, d, JM end — 1 mono-1 ketone [real .53 (3H, sm), 3.57 2H, m), = 4.78Hz) 95 (1H, m = 8.90Hz) 7.42Hz), an iso-D-quinoline one, one 1-one-165- (161) 200536830

〇

2-Bromo-5-methylbenzoic acid prepared by the method disclosed in WO 2002/083066 or US4282365, and 5-bromo-2, N-dimethylbenzyl was prepared by a method similar to that in Step A of the Example. Lamine. Using this as a starting material, 7-bromo-3-(2-trifluoromethylphenyl)-2H-isoDquinolin- 1-one was synthesized by a method similar to that in Step B of Example 1. W-NMR (270MHz, CDC13) 5 (ppm): 6.48 (1H, s), 7.45 (lH, d, J = 8.5Hz), 7.53-7.56 (1Η, π),

7.61-7.72 (2H, m), 7.76-7.84 (2H, m), 8.53 (1H, d, J = 1.98Hz), 8.87 (lH, brs) ESI (LC-MS positive) m / z386 (M + H), 3 70 (M + H + 2).

30 mg (0.08 mmol) of 7-bromo-3- (2-trifluoromethylphenyl) -2H-isoD | linen-1 monoketone prepared in step A, 18.6 mg (0 · 0 9 8 mm ο 1) of copper (I) iodide, 3 9.1 mg (0 · 2 0 4 mm ο 1) of -166- (162) 200536830 Acetic acid is absolutely suspended in dried 0.5 m L dimethylformamide Add ammonium amine, add 2 0 // L of a 40% methylamine-methanol solution, and stir at 100 ° C for 1 night. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after the extract was concentrated was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain 15.4 mg (61%) of 7-methylamino-3- (2-trifluoro (Methylphenyl) -2H-isoD-Quelin-1.

] H-NMR (270MHz, CDC13) ^ (ppm): 1.25 (1H, s), 2.98 (3H, s), 6.44 (1H, s), 7.02 (1H, dd, j = 2 · 6,8 · 6Ηζ), 7.40 (lH, d, J = 8.6Hz), 7.50-765 (4H, m), 7.80 (lH, d, J = 7.9Hz), 8.29 (1Η, η) ESI (LC-MS positive) m / z319 (M + H). The following compounds (Examples 120 to 130) were prepared using 7-amino-3- (2-trifluoromethylphenyl) ~ 2H ~ isod-quinolin-j-one as the starting material, &Amp; [Example 120]

[1 monooxo- 3-(2-trifluoromethylphenyl)-1 D quinoline- 7 -yl] propyl carbamate

卞 Ο,. Also, iH-NMR (400 MHz, CDC13) δ (ppm): 1.00 (3Η -167- 200536830 (163), J 2 7.2Ηζ), 1.58-1.78 (2Η, m), 4.17 (2Η, t J, 6.8Hz), 6.48 (lH, s), 6.96— 7.00 (lH, m) ^ 7.54—7.69 (4H, m), 7.8.2 (1 H, d, J 7.2 Hz) , 8.05- 8.30 (2H, m), 8.56 (lH, brs) ESI (LC-MS positive) m / z391 (M + H). [Example 1 2 1]

[1 monooxo- 3-(2-trifluoromethylphenylline- 7 -yl] isopropylaminoformate 1, 2 -dihydroisopropyl

〇 j-NMR (400MHz, CDC13) (5 (ppm): 1.34 (3H, d, J = 6.4Hz), 1.37 (3H, d, J = 6.4Hz) ^ 5.03-5.09 (lH, m), 6.48 ( lH, s), 6.75-6.85 (lH, m) ^ 7.52 • — 7.69 (4H, m), 7.82 (lH, d, J = 8.0Hz), 8.09 (1Η, d, J = 2.4Hz), 8.12 (lH, brs), 8.41 (lH, brs) ESI (LC-MS positive type) m / z391 (M + H). [Example 122] [1-oxo-3-(2-trifluoromethyl) Phenyl) -1,2-dihydroisoD-quinolin-7-yl] isobutylcarbamate-168- (164) 200536830

] H-NMR (270MHz, CDC13) 5 (ppm): 0.99 (6H, d

, J = 6.6Hz), 1.95-2.06 (1H, m), 4.00 (2H, d, J -6.6Hz), 6.49 (1H, s), 6 · 9 3 — 7 · 0 2 (1 H, m) , 7.55-7.70 (4H, m), 7.82 (lH, d, J = 7.3Hz) ^ 8.09

—8.20 (2H, m), 8. 5 3 (1 H, b r s) ESI (LC-MS positive type) m / z405 (M + H). [Example 1 2 3] [1-oxo-3- (2-trifluoromethylphenyl) -1,2-dihydroiso-D-quinoline- 7-yl] amyl carbamate

] H-NMR (270MHz, CDC13) 5 (ppm): 0.92 (3H, t

»J-6.60Hz), 1.35-1.38 (4H, m), 1.65-1.72 (2H, m), 4.19 (2H, t, J = 6.60Hz), 6.49 (1H, s), 7.11 (lH , S), 7.56 (2H, d, J = 8.58Hz), 7.60-7.70 (2H, m), 7.82 (lH, d, J = 7.92Hz), 8.11-8.16 (2H, m), 8.80 (1H, brs) EI-MSm / z418 (M +). -169- (165) 200536830 [Example 1 2 4]

[1-oxo- 3- (2-trifluoromethylphenyl)-1 quinoline- 7 -yl] benzyl aminoformate

j-NMR (270 MHz, CDC13) 5 (ppm): 5.23 (2H, s

), 6.49 (lH, s), 7.31-7.43 (6H, m), 7.52-7.69 (4H, m), 7.81 (lH, d, J = 7.26Hz), 8.10-8.20 (2H, m), 8.82 ( 1H, brs)

El-MS m / z 43 8 (M +). [Example 1 2 5] [1 Monooxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] allyl carbamate

] H-NMR (400MHz, CDC13) 5 (ppm): 4.70 — 4.73 (

2H, m), 5.29 (lH, d, J = 10.4 Hz), 5.39 (lH, d, J = 16.0 Hz) ^ 5.95-6.0 5 (1 H-m), 6.49 (lH, s),

6.97-7.01 (lH, m), 7.54- 7.69 (4H, m), 7.82 (1H, d, J = 8.0Hz), 8.05 (2H, m), 8.43 (1H, brs) ESI (LC-MS positive type M / z 389 (M + H). -170- (166) 200536830 [Example 1 2 6] [1 monooxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoDquinoline-7-yl] amine Butadienyl carbamate

j-NMR (270MHz, CDC13) δ (ppm): 1.86 (3H, s), 4.77 (2H, s), 6.43 (lH, s), 7.62-7.81 (5H, m), 7.87 (lH, d, J = 7.9Hz), 8.37 (lH, s), 10.14 (1 H, s), 1 1.53 (1 H, brs) ESI (LC-MS positive) m / z401 (M + H). [Example 1 2 7] [1 monooxo-3- (2-difluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] carbamic acid 2- (2-methyl Ethoxyethoxy) ethyl ester

h-NMR (270MHz, CDC13) (5 (ppm): 3.38 (3H, s), 3.55-3.58 (2H, m), 3.66-3.69 (2H, m), 3.76-3.79 (2H, m), 4.36 — 4.39 (2H, m), 6.49 (lH, s), 7.33 (lH, s), 7.55 (2H, d, J = 8.57Hz) »7.60-

7.70 (2H, m), 7.81 (lH, d, J = 7.25Hz), 8.12 (1H-171 (167) 200536830, brs), 8.14 (1H, s), 8.78 (1H, brs)

El — MS m / z 45 0 (M +). [Example 1 2 8] [1-oxo-3- (2-difluoromethylphenyl) -1,2-diarginoisoquinoline-7-yl] aminocarboxylic acid 3-methoxy 1,2,2-dimethylpropyl ester

] H-NMR (400MHz »CDC13) (5 (ppm): 0.98 (6H, s), 3.19 (2H, s), 3.33 (3H, s), 4.04 (2H, s), 6.49 (lH, s), 7.10— 7.20 (lH, m), 7.55-7.69 (4H, m), 7.82 (lH, d, J = 7.2Hz), 8.10— 8.20 (2H, m), 8.6 1 (1H, brs) ESI ( LC-MS positive) m / z449 (M + H).

[Example 129] [1-oxo-3- (2-dioxomethylphenyl) -1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid 2-methoxyethyl ester

] H-NMR (270 MHz, DMSO — d6) δ (ppm): 3.30 (3Η, s), 3.59 (2H, t, J = 4.6Hz), 4.25 (2H, t, J = -172- (168) 200536830 4 · 6Ηζ), 6.42 (lH, s), 7.60-7.88 (6H, m), 8.40 (lH, s), 10.10 (lH, s), 11.51 (lH, s) ESI (LC-MS positive) m / z407 (M + H). [Example 1 3 0] [1 Monooxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid 2-benzyloxy Ethyl ester

W-NMR (400MHz, CDC13) 5 (ppm): 3.75 (2H, t, J = 4.7Hz), 4.39 (2H, t, J = 4.7Hz), 4.60 (2H, s), 6.48 (lH, s), 7.02-7.12 (lH, m), 7.29-7.37 (5H, m), 7.52-7.69 (4H, m), 7.82 (lH, d, J = 7.2Hz), 8.05-8.15 (2H, m) , 8.49 (lH, brs) ESI (LC-MS positive) m / z483 (M + H). [Example 1 3 1] [1 Monooxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoquinoline- 7-yl] aminocarboxylic acid 2-hydroxyethyl ester

[1 — -173- (169) 200536830 oxo-3 — (2-trifluoromethylphenyl) —1 obtained in Example 1 3 0 of 4 4.9 mg (0 · 0.93 mm ο 1) 2,5-Dihydroisoquinoline-7-yl] aminocarboxylic acid 2-benzyloxyethyl ester in methanol solution (5 ml) was added with 4.5 mg of 10% Pd / C, at room temperature under a hydrogen atmosphere. Stir vigorously for 2 hours and 20 minutes. After filtering insoluble matters, the residue obtained after concentrating the filtrate was purified by silica gel column chromatography (ethyl acetate) to obtain 33 mg (90%) of [1-oxo-3- (2-trifluoromethylphenyl) ) —Ι, 2-dihydroisoquinoline-7-yl] aminocarboxylic acid 2-hydroxyethyl ester.

W-NMR (400MHz, CDC13) 5 (ppm): 2.68 to 2.78 (1H, m), 3.83 to 3.93 (2H, m), 4.33 (2H, t, J = 4.6Hz), 6.51 (1H, s ), 7.5 3 — 7.6 7 (5 H, m), 7.79 (lH, d, J = 7.3Hz), 8.14—8.24 (2H, m), 8.94 (1Η, brs) ESI (LC—MS positive Type) m / Z393 (M + H) 〇 [Example 1 3 2]

[1 monooxo-3- (2-trifluoromethylphenyl) -i, 2 ~ monochloroquinolin-7-yl] aminocarboxylic acid (R)-2, 3-bisphenoxypropane

0.50 mL (1.98 mmol) of (S) — (-N, N-diisopropane) was added dropwise —> benzylpropanediol, 0.69 m L (3.9 6 mm ο 1) of propyl The ethylamine mixture was dissolved in 5 ml of Dichloromethane-174- (170) 200536830 2 9 4 mg (0.9 9 mm ο 1) of triphosgene in 5 ml of dichloromethane solution and stirred at room temperature. 30 minutes. After concentrating the reaction solution, it was dissolved in 5 ml of dichloroformamidine as a dichloromethane solution of (R) -2,3-bis-phenoxyoxypropyltrichloroformate (1.98). mmol / 5mL). 100 mg (0.3 3 mm ο 1) of 7-amino-3- (2-difluoromethylphenyl) -2H-isoDquinoline prepared in Example 3 8 was prepared. 1_ketone,

0.29 mL (1.65 mmol) of a mixture of N, N-diisopropylethylamine was dissolved in 3 mL of dichloromethane, and the above-mentioned 2.5 mL of trichloroformate solution was added in an ice bath, followed by stirring at room temperature for 20 minutes. hour. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the residue obtained after concentration was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain 49 mg (25%) of light yellow. [1 monooxo-3-(2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid (R)-2,3- Diphenoxypropyl ester. ] ΗΝΜΙΙ (270MΗζ, OM80- (16) δ (ppm): 3.60 (2H, ddd, J = 12 · 0, 1 〇 · 1,5 · 3Ηζ), 3.84 (1H, m), 4.27 ( lH, dd, J = 11.6, 5.3Hz), 4.38 (lH, dd, J = 11.6, 4.0 Hz), 4.50 (2H, s), 4.63 (2H, s), 6.48 (1H, s), 7.23-7.33 (lH, m), 7.45-7.60 (4H, m), 7.74 (1 H, d, J = 8.2 Hz), 7.93 (1H, s), 8.17 (1H, brs), 9.72 (1H , Brs) ESI (LC-MS positive type) m / z603 (M + H). The compounds shown below (Examples 1 3 3 to 1 3 7) are obtained from Example 3 8 -175- (171) 200536830 7-Amino-3— (2-difluoromethylphenyl) -2H-isoDquinolin-1-one with the appropriate alcohol or thiol as the starting material, as in Example 1 3 2 [Example 1 3 3] [Example 1 3 3] [1 monooxo-3- (2-difluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] amine 2-benzyloxy-1,1-benzyloxymethyl ethyl

Ο

1 H-NMR (270MHz, DMSO-d6) (5 (ppm): 3.71 (4H, d, J = 5.00Ηζ), 4.49 (2H, d, J = 1 2.0Hz), 4.54 (2H, d J, 12 · 2Ηζ), 5,20 (lH, dt, J = 5.0, 5.0Hz),

6.45 (lH, s), 7.24— 7.31 (10H, m), 7.50-7.63 (4H, m), 7.75 (1 H, d, J = 8.2Hz), 7.83 (1H, brs), 8.12 (1H , D, J = 2.3 Hz), 8.17 (1H, d, J = 8.4 Hz), 9.89 (1H, brs) ESI (LC-MS positive) m / z603 (M + H). [Example 1 3 4] [1 Monooxo-3 — (2-difluoromethylphenyl) —1,2-dihydroisoxolinoline 7 —yl] cyclohexyl methylcarbamate -176 -(172) 200536830 cr and 0 κ

] H-NMR (270MHz, DMSO— d6) 5 (ppm): 0 · 97 —

1.25 (6H, m): 1.64— 1.76 (5H, m), 3.93 (2H, d, J -6.4Hz), 6.40 (1H, s), 7.5 8-7.8 6 (1H, m), 8.38 (lH, d, J = 2.3Hz), 9.92 (lH, s), 11.50 (1Η

ESI (LC-MS positive) m / z445 (M + H). [Example 1 3 5] [1 Monooxo-3- (2-difluoromethylphenyl) -1,2-dihydroisoDquinoline- 7-yl] carbamic acid cyclohexane

j-NMR (270MHz, DMSO-d6) (5 (ppm): 1.15- 1.99 (10H, m), 4.67 (lH, m), 6.41 (lH, s), 7.59

—7.88 (6H, m), 8.40 (lH, d, J = 2.2Hz), 9.90 (lH, s), 1 1 · 4 8 (1H, s) ESI (LC—MS positive) m / z431 ( M + H). [Example 1 3 6] [1 monooxo-3- (2-trifluoromethylphenyl) -1,2-dihydroiso-177- (173) 200536830 quinoline-7-yl

] Ν-ΝΜΙΙ (270ΜΗζ, ϋΜ30- d6) 5 (ppm): 5.06 (2H

, S), 6.41 (lH, s), 6.60 (lH, s), 7.59-7.87 (9H, m), 8.40 (1H ^ d, J = 2.3Hz), 10.0 (1H ^ brs)

ESI (LC-MS positive type) m / z429 (M + H). [Example 1 3 7] Mono-1,2-dihydroiso [1-oxo-3 — (2-trifluoromethylphenyl) quinolin-7 mono] thioaminocarboxylic acid S monoethyl ester

iH-NMR (270MHz, DMSO — d6) (5 (ppm) · 1.29 (3H, t, J = 7.3Hz), 2.92 (2H, dd, J = 14.5, 7.3Hz),

6.44 (lH, s), 7.62 — 7.89 (6H, m), 8.48 (lH, d, J -2.3Hz), 10.60 (lH, s), 11.55 (lH, s) ESI (LC-MS positive type ) M / z393 (M + H). [Example 1 3 8] [1 monooxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoowolin-7-yl] carbamic acid (R) -2, 3-Dihydroxypropyl-178- (174) 200536830

OH 〇 2 1 mg (0.0 4 3 mm ο 1) of [1-oxo-3- (2-trifluoromethylphenyl) -1,2-dihydroiso D Quinoline- 7-yl] aminocarboxylic acid (R) — 2,3-bisphenoxypropyl ester, 5

A mixture of mg (0.036 mmol) of palladium hydroxide and 0.2 mL (3.49 mmol) of acetic acid was suspended in 3 mL of ethanol and stirred for 2 hours under a hydrogen atmosphere. After filtering the reaction solution through celite, the residue obtained after concentration was purified by silica gel column chromatography (dichloromethane: methanol = 1 0: 1) to obtain 18 mg (100%) of [1— Oxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoquinoline-7-yl] aminocarboxylic acid (R) -2,3-dihydroxypropyl ester.

] H-NMR (270 MHz, DMSO-d6) (5 (ppm): 3.42 (2H, m), 3.73 (lH, dt, J = 5.0, 5.0Hz), 4.03 (lH, dd, J = 11.0, 6.4Hz ), 4.17 (1H, dd, J = 11.〇, 4 · 2Ηζ), 5.40 (2H, brs), 6.41 (1H, s), 7 · 5 9 — 7 · 8 8 (6 H, m), 8.41 (lH, s): 1 (K〇4 (1H, s), 11.50 (lH, brs) ESI (LC-MS positive type) m / z 423 (M + H). [Example 1 3 9] [ 1 monooxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisotope | linen-7-yl] aminocarboxylic acid 2-hydroxy-1-hydroxymethylethyl-179 -(175) 200536830

[1-oxo-3- (2-trichloromethylphenyl) -1,2-monoaminoisoquinoline-7-yl] aminocarboxylic acid synthesized in Example 1 3 3 The oxy-1,1-benzyloxymethyl ethyl ester was used as a starting material, and was synthesized by a method similar to that in Example 138.

iH-NMR (270MHz, DMSO-d6) (ppm): 3.58 (2dd, dd, J = 11.6, 5.5Hz), 3.63 (2H, dd, J = 11.6, 5.5Hz), 4.77 (1H, dt, J = 5.5, 5.5Hz), 5.70 (2H, brs), 6.41 (lH, s), 7.59-7.88 (6H, m), 8.42 (lH, s), 10.02 (lH, s), 11.50 (lH, brs) ESI (LC-MS positive) m / z423 (M + H). [Example 140]

[3 -— (2-Molein-4 4-phenylphenyl) —1—oxo—1,2—dichloroisoquinoline—7—yl] Ethyl carbamate Step A 7 —Amine —3— (2-morpholin-4 monophenyl) -2H-isoD-quelin-1-1-one

The 7-chloro-3-(2 -morpholine-180- (176) 200536830 -4 monophenylphenyl) -2H-isoD-quinoline-1 monoketone synthesized in Example 9 7 Step A was used as an example. 3 8 is obtained by a similar method. iH-NMR (400MHz, CDC13) (5 (ppm) 4H, m), 3.84 — 3.90 (4H, m), 4.0.66.67 (1H's) '7.05 (1H, dd, J = 2.0, --7.20 (2H, m), 7.35— 7.45 (2H, m) lH, m), 7.64 (lH, d, J = 2.4Hz), 10. Lu ESI (LC-MS positive) m / z 322 (M + H)

Step B! Raw materials to be compared with: 2.9 5-2.99 ((2 Η, brs), 7.1Hz), 7.10, 7.5 5-7.5 9 (86 (1H, brs) 1, 2 -dihydroiso [ 3- (2-MoD-Lin-4-ylphenyl) -1-oxoisoDquinoline-7-yl] carbamate

Group) ~ 2H-isoD-quinolinone- 1-one as a raw material 'was synthesized by a similar method. 1 H-NMR (400MHz, CDC13) 5 (PPm), J = 7.2Hz), 2.98 (4H, t, J 2 4.4Hz)? = 4.4Hz), 4.27 (2H, q, J: 7.2Hz)

), 6.8 1 (1H, brs), 6. · 9 9-7.2 5 (2 H 7.43 (lH, m)), 7.56 — 7.63 (2H, m),) 5 8.20 (1 H ^ brs),: 10.95 (lH, brs) Morin-4 monophenylbenzene Example 5 Class 7: 1.35 (3H, t, 3.88 (4H, t, 6.72 (1H, s, m)), 7.37-8.04 (1H, brs -181-(177) 200536830 ESI (LC-MS positive type) η / ζ 394 (M + Η). [Example 1 4 1] radical one 1, 2 — [3 — (4 monofluoro one 2 — three Fluoromethylphenyl) 1-oxodihydroisoquinoline-7-yl] aminocarbamate

Synthesized by a method similar to Example 1 40] H-NMR (400MHz »CDC13) δ (ppm): 1, J = 6.8Hz), 4.27 (2H, q, J = 6.8Hz), 6), 6.85 (1H, brs), 7 · 3 5 — 7 · 3 9 (1H, m 7.5 7 (3H, m)), 8.09 (1 H, brs), 8.17 (1: 8.45 (1H, brs) ESI (LC— MS positive type) m / z395 (M + H). [Example 142] [1 monooxo-3- (2-trifluoromethoxyphenyl) isoquinoline-7-yl] ethyl carbamate Ester ο .35 (3Η, t • 46 (1Η, s), 7.5 1 — ί 5 brs),, 2 —dihydro

35 (3H, t was synthesized by a method similar to that in Example 1 41 to obtain H-NMR (270 MHz, CDC13) δ (ppm): 1. -182- 200536830 (178) 1H, s, 8.08, J = 7.1Hz), 4.28 (2H, q, J = 7.1Hz), 6.66 (), 6.83—6.93 (lH, s), 7.40—7.61 (5H, m) — 8 · 1 3 (2H, m) , 8.64 (1 H, brs) ESI (LC-MS positive) m / z393 (M + H).

[Example 1 4 3] Methyl [1 monooxo- 3-(2-trifluoromethylphenyl)-1, hydrogen isoquinoline-7 -yl] urethane 2-di

7-methylamino-3— (fluoromethylphenyl) —2H—isoxoline-1—one obtained in Step B of Example 1 1-9 as a starting material was synthesized in a similar manner to that in Example 5 and 7 Got. W-NMR (270MHz, CDC13) δ (ppm): 1.27 (, J = 7.1Hz), 3.41 (3H, s), 4.22 (2H, q, J =), 6.52 (lH, s), 7.55-7.72 ( 5H, m) ^ 7.83 dd, J = 1.7, 8.1 Hz), 8.20 (1H, d, J = 2.3 Hz) (1H, brs) ESI (LC-MS positive type) m / z391 (M + H). [Example 144] Methyl [1-oxo-3- (2-trifluoromethylphenyl) -1, hydrogen isoquinoline-7-yl] aminocarboxylic acid 2-hydroxyethyl 2-tri With 3H, t: 7.1Hz (1H,, 8.72 -183- (179) 200536830

The 7-methylamino- 3-(fluoromethylphenyl)-2H-isoDquinoline- 1-one obtained in Step B of Example 1 19 as the starting material was used as the starting material. A method similar to that in Example 1 31 was obtained from f. ] H-NMR (500 MHz, CDC13) 5 (ppm): 2.47 (brs), 3.43 (3H, s), 3.78-3.88 (2H, m), 4

4.33 (2Η, π), 6.52 (lH, s), 7.53-7.60 (2H, 7.63-7.71 (3H, m), 7.82-7.84 (1Η, π, 8 1H, d, = 1.81Hz), 8.72 (1H, brs)

El-MS m / z 406 (M +). [Example 1 4 5] 3- (4-Hydroxy-2-methylphenyl) -7- (3-hydroxypiperidinyl) -2H-isoDquinoline-1 1-ketone 2-trisynthesis 1H, • 29 —, m) .26 (one 1 one

Example 9 17 mg (0 · 0 4 6 6 mm ο 1) of 7-hydroxypiperidine-1 -yl)-3-(4-methoxy-2-methylbenzene 3 2H-iso To a solution of quinoline-one monoketone in dichloromethane (0.5 mL), 0.070 mL (0.07 0 mmol) of 1M boron tribromide (3-)-to-dichloro-184- (180 200536830 A After stirring the 'bath, liquid' at the same temperature for 30 minutes. After adding saturated aqueous sodium carbonate carbonate solution, the mixture was extracted with dichloromethane / methanol (5: 1). The solution was extracted and concentrated by MMT. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1 ~ 10: 1) to obtain 10 mg (61%) of 3-(4-monohydroxy-2 -methylphenyl) as a light brown solid. )-7- (3-hydroxypiperidine- 1-yl) ~ 2H-Iso-I] quinoline-; 1-one.] H-NMR (270MHz ^ CD3OD) (5 (ppm): 1.30-1.43

(lH, m) ,: 1.52—i.66 (lH, m) ,: 1.77—1.95 (2Η, η) '2.17 (3Η js), 2.70 (1H, dd, J = 11.5, 8.5 Hz ), 2.76 — 2.85 (1H 5 m), 3.41 — 3.50 (1H, m), 3.60 — 3.76 (2H, m), 6.36 (1H, s), 6.60 (1H, dd, J = 8.5

, 2.5Hz), 6.63 (lH, d, J = 2.5Hz), 7.07 (lH, d, J = 8.5Hz), 7.38 (lH, dd, J = 9.0, 2.5Hz), 7.44 (1Η, d , J = 9.0Hz), 7.61 (lH, d, J = 2.5Hz) ESI (LC-MS positive type) m / z351 (M + H).

[Example 146] 3- (2-chlorophenyl) -7-morpholine-1 4-yl-1 2H-isoquinoline-1 1-one

Ο

Using the 2, N, N-trimethyl-5-morpholine-4-ylbenzamide obtained in Example 8 0 step B as a raw material 'is similar to Step B -185- (181) 200536830 of Example 1 Method. ] H-NMR (400MHz, CDC13) (5 (ppm): 3.32 (4H, m), 3.9 1 (4H, m), 6, 57 (1H, s), 7.34 — 7.4 1 (3H, m ), 7.48-7. .53 (3H, m), 7.81 (1 H, d, J 2.9Hz), 8.49 (1 Η, brs) ESI (LC-MS positive type) m / z341 (M + H).

[Example 1 4 7] 2-Methoxy-N- (1-oxo-3-phenyl-phosphino-7-yl) acetamidine 1, 2-dihydroisoquine

5 mL of 2-benzyloxy-N- (1-oxo-3-phenyl-1,2-dihydroisoD-quinolin-7-yl) acetamidin prepared in Example 60 In a methanol solution, dichloromethane was added until the solution became transparent, 10 mg of 10% Pd-C was added, and the mixture was stirred for 8 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain 7.8 mg (46%) of 2-hydroxy-N- (1-oxo-3-phenyl-1,2-dihydroisoquinone) as a yellow solid. Phenyl-7-yl) acetamide.

H-NMR (270MHz, DMSO-d6) (5 (ppm): 4.04 (2H, s), 5.81 (lH, brs), 6.68 (lH, s), 7.44-7.52 (

2H, m), 7.67 (lH, d, J = 8.58Hz), 7.77— 7.80 (2H, m), 7.97 (lH, dd, J = 1.98, 8.58Hz), 8.68 (1H, -186- (182 ) 200536830 d ^ J = 2.3 1 Hz), 11.46 (lH, m) ESI (LC-MS positive type) m / z293 (M- H +). [Example 1 4 8] 3 -phenyl- 7- ((2S, 3R)-2,3,4-trihydroxybutylamino)-2

〇Η

OH ΟΗ

The 7-amino- 3 -phenyl- 2 fluorene-isoquinoline- 1-one prepared in Example 39 was used to synthesize JH-NMR (2 70 MHz ^ CD3) by a method similar to that in Example 41 1 〇D) (5 (ppm): 3.24 (1H, dd, J = 7.59, 12.87Hz), 3.57-3.64 (2H, m), 3.68 (

lH, d, J = 5.94Hz), 3.77-3 · 86 (2Η, η) ^ 6.84 (1H

, S), 7.19 (1H, dd, J = 2.3 1, 8.58Hz), 7.37-7.52 (5H, m), 7.66 — 7.70 (2H, m) FAB-MS ni / z 341 (M + H) . [Example 1 4 9] 7- (2,2-Dimethylhydrazinyl) -3- (2-Difluoromethylphenyl)-2 Η-IsoD-Querin-1 1-·· -187- ( 183) 200536830

7-chloro-3 methylphenyl) -2H-iso (I quinoline-1 monoone) prepared in step B of Example 1 was used as a raw material, and a reaction similar to that in Example 4 was used for synthesis.] H-NMR (2 7 0MHz, CDC13) d (ppm):), 4.54 (1H, s), 6.44 (1H, s), 7.32 = 2.5, 8.6Hz), 7.44 (1H, d »J = 8.6Hz) (3H , M), 7.76— 7.83 (2H, m), 8.58 (1 ESI (LC-MS positive) m / Z348 (M + H). [Example 1 5 0] (2-Difluorofuranine and implementation 58 (6H, s1H, dd, J 7.50-7.68, brs) group) 3— (2-trifluoro / methylphenyl) —7— (1,2,2—trione 2H—isoD-quinoline— 1-one

To 1 mg of 7- (2,2-yl) -3- (2-trifluoromethylphenyl)-2H-isoI] quinoline in 28 mg of Example 149, 0.1 mL of Acetic acid, 26.2 // morpholine aqueous solution, 25 · 3 mg (0.403 mmOl) of cyanotri, and stirred at room temperature overnight. Saturated bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The concentrated ear extract residue was subjected to silica gel column chromatography (ethyl acetate: hexanedi 1: 2 ^ -188- -dimethylhydrazine-1 monoketone L 37%. Sodium hydroborate 3 aqueous solution {Liquid obtained '2: 1) pure (184) (184)

200536830 After the conversion, 25.5 mg (8.8%) of 3 methylphenyl)-7- (1,2,2-trimethylhydrazino) line-1-one was obtained as a pale yellow solid. 1H-NMR (270MHz, CDC13) δ (ppm):), 2.92 (3H, s), 6.46 (lH, s), 7.46 (8.9Hz), 7.50-7.67 (4H, m), 7.72 (1Η ,, 8 · 9Ηζ), 7.76 — 7.83 (lH, m), 8.33 (1Η ESI (LC-MS positive) m / z 362 (M + H). [Example 1 5 1] 7— (N —diphenylmethylenehydrazine) — 3 — (2—trifluoro—2H—isoquinoline—1—one —— (2—dirang—2 Η —isoquine L52 (6Η, s 1Η, d , J = dd, J = 2.6, brs) methylphenyl)

The 7-chloro-3 methylphenyl) -2H-isoquinoline-1 1-one prepared in Step B of Example 1 was used as a raw material, and the reaction was similar to that obtained in Example 4 and synthesized. W-NMR (2 70 MHz, CDC13) 5 (ppm):), 7 · 30— 7.40 (5H, m), 7.47 — 7 · 70 (9Η — 7.84 (4Η, m)), 8.36 ( 1Η, brs) ESI (LC-MS positive type) m / z4 84 (M + H). [Example 1 5 2]-(2-trifluoro through and implementation • 47 (1H, sm), 7.7 1- 189- (185) 200536830 1 monomethyl-3— [1 monooxo-3— (2-difluoromethylbenzyl), 2-dihydroisoquinoline-7-yl] urea

20.8 mg (0.05 mmol) of Example 1 14 7-Iodine 3- (2-trifluoromethylphenyl) -2H-isoquinololine-1 prepared in step A 14

Monoketone, 2.2 mg (0.0025 mmol) of tris (diphenylmethyleneacetone), 4.2 mg (0.0075 mmol) of 9,9-dimethyl-1 4 '5-bis (diphenylphosphino) , 22.8 mg (0.07 mmol) of carbonic acid, 4.44 mg (0.06 mmol) of methyl urea in 1,4-dioxane solution 0.5 mL, and stirred at 1 10 ° C overnight. After the reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The residue obtained by concentrating the extract was purified by silica gel column chromatography (dichloromethane institute: methanol = 2 0: 1) to obtain 1 · 7 mg (9%) of a colorless solid 1-methyl 3-[1 —Oxo-3— (2-trifluoromethylphenyl) -1,2-dihydroisoquinolin-7-yl] urea. 1 Η-NMR (270 MHz, DMS 0-d6) δ (ppm): 2.67 (3Η, d, J = 4.6Hz), 6.25-6.35 (lH, m), 6.38 (1H , S), 7.54 (lH, d, J = 8.6Hz) 5 7.57— 7.90 (5Η »m),

8.28 (1H 5 d ’J = 2.3Hz)’ 9.04 (1H, brs), 11.40 (1H, brs) ESI (LC-MS positive type) m / z362 (M + H). -190- (186) (186) 200536830 [Example 1 5 3] N-methyl-N- [1 monooxo-3- (2-trifluoromethylphenyl) -1,2-dihydro Isoquinoline-7-yl] formamidine

The 7-methylamino-3- (2-trifluoromethylphenyl) -2H-isoDquinoline-1-one obtained in Example 1 1 Step B was used as the starting material. 7 similar methods were obtained by synthesis. ] H-NMR (270MHz, CDC13) 5 (ppm): 3.41 (3H, s), 6.54 (lH, s), 7.47-7.74 (5H, m), 7.79-7.88 (lH, m ), 8.14 (lH, d, J = 2.6 Hz), 8.63 (lH, s), 9.37 (1 H, brs) ESI (LC-MS positive) m / z347 (M + H). [Implementation, Example 154] N— [1-oxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoDquinoline-7-yl] benzamide

Using 7-amino-3- (2-trifluoromethylphenyl)-2H-isoquinoline-1 monoketone prepared in Example 38 as a starting material, a method similar to that in Examples 5-7 was used. Synthesized. -191-(187) 200536830

W-NMR (270 MHz, DMSO — d6) o (ppm): 6.48 (1H, s), 7.54—7.82 (8H, m), 7.89 (lH, d, J = 7.8Hz), 8.05 (2H, dd) , J = 7.8, 2.1 Hz), 8.75 (lH, d, J = 2.1 Hz), 10.59 (lH, s), ll: 57 (lH, s) ESI (LC-MS positive) m / z409 ( M + H). [Example 1 5 5]

N- [1-oxo-3- (2-trifluoromethylphenyl) -1,2-dihydroisoD-quinoline- 7-yl]-2-thiophene 2- 2-ethylacetamide

0

The 7-amino-3- (2-trifluoromethylphenyl) -2H-isoquinoline-1 monoketone prepared in Example 38 was used as a starting material, by a method similar to that in Examples 5-7. Synthesized. W-NMR (270MHz, DMS0 — d6) δ (ppm) · 3.95 (2Η, s), 6.45 (1H, s), 7.00-7.04 (2H, m), 7.42 (1H, dd, J = 5.0, 1.4Hz), 7.62— 7.80 (4H, m), 7.86 (1H, d, J = 8.7Hz), 7.93 (1H, dd, J = 8.7, 2.1Hz), 8.55 (lH, d, J = 2.1Hz), 10.55 (lH, s), 11.54 (1H, s) ESI (LC-MS positive type) m / z429 (M + H). [Example 1 5 6] -192- (188) 200536830 N — [1-] Ethylamine oxo- 3 -phenyl-1,2-dihydroisoline- 7 -yl

The 7-amino- 3 -phenyl- 2H-iso-D-quinolin- 1 -one prepared in Example 39 was used as a starting material, and synthesized by a method similar to that in Example 5 7.

] H-NMR (270MHz ^ DMSO- d6) (5 (ppm): 2. 1 0 (3H, s), 6.87 (lH, s), 7.40-7.52 (3Η, η), 7.65 (lH, d) , J = 8.4Hz), 7.78 (2H, d, J = 8.4Hz), 7.86 (lH, d, J = 8.4Hz), 8.52 (lH, s), 10.22 (lH, s), 11.43 (1H, s ) EIMSm / z2 7 8 (M + H).

6-chloro-1 7-morphine-1 4-yl-1 3- (2-dichloromethylphenyl) -2H

Iso-D is called 1 1-wake up Step A 2, N-dimethyl- 5 -morpholine-4 -yl benzamidine

Using 5-chloro-2, N-dimethylbenzamide prepared in step A of Example 1 as the starting material, the method was similar to the method -193-(189) 200536830 of Step 80 in Example B. Synthetic. h-NMR (400MHz, CDC13) 5 (ppm): 2.34

), 2.93 (3H, d, J = 5.2Hz), 3.11 (4H, t, J), 3.85 (4H, t, J = 4.6Hz), 5.71 (lH, brs) (1H, dd, J = 2.4 ^ 8.4Hz), 6.91 (1H, d, J =, 7.11 (1H, d, J = 8.4Hz)) ESI (LC-MS positive type) m / z235 (M + H). 3 Η, s: 4 · 8Ηζ 5 6.87 • 2Hz)

Step B Amine and 4-chloro-2, N-dimethyl-5-morpholine-4 4-ylbenzidine 2-chloro-6, N-dimethyl-3 3-morpholine-4 Benzamidine:

Dissolve 100 mg (0.427 mmol) of dimethyl-5-morpholine-4-ylbenzidine in step A in 3 mL of dimethylformamide, and add 63 mg ( 0.47 mmol) chlorosuccinimine's stirring at 50 ° C for 1 hour. The reaction mixture was concentrated with water and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained after concentrating the extract was purified by silica chromatography (ethyl acetate ·· dichloromethane = 1: 5) to obtain 54.5 mg (47%) of 4 monochloro-2, N-dimethyl-5 —4-Monyl benzamidine, 46 mg (40%) of a colorless solid of 26, N-dimethyl-3-morpholine-4 4-yl benzamidine. 2, Ν — Ν, Ν — of Ν, after adding, the column is colorless and solid. Monomorpholine ―chloro- -194-

200536830 (190) 4 monochloro-2 'N — monomethyl-5 —morphine — 4-benzylamine ^ -NMR (400MHz ^ CDC13) δ (ppm): 2.36), 2.97-3.03 (7H, m), 3.87 (4H, t, J = 4.5.72 (lH, brs), 7.03 (lH, s), 7.23 (lH, s) ESI (LC-MS positive) m / z269 (M + H). 2 —Chloro-6, N — — • methyl — 3 —Morin — 4 monobenzylamine 1 H-NMR (400MHz, CDC13) 5 (ppm): 2.3 8), 3.00 (4H, t, J = 4.6Hz), 3.04 (3H, d, ·), 3 · 86 (4H, t, J = 4.4Hz), 5.64 (1H, brs (1H, d, J = 8.4Hz), 7.08 (1H, d, J = 8.4Hz) ESI (LC-MS positive type) ni / z269 (M + H).

Step C 6 -Chloro-7-Morim-4-yl-3- (2-Dichloromethylbenzene-Iso-D-quinolin-1-one

Dilute 167 / iL (0.3 mmol) of a 1.8M lithium diisopropylhydrazone solution with 1.5 mL of THF and drop dropwise 27 mg (0.10 mmol) of 4-chloro-one at 78 ° C. A solution of 2, N-dimethylmorpholine-4 monobenzamide in 1 mL of THF. Here mg (0.10 mmol) of 2- (trifluoromethyl) benzonitrile (3H, s 4Hz), (3H, s = 4.8 Η z, 6.96

) -2H I Amine THF 丨 B 5-17 ml of -195- (191) 200536830 THF solution was added dropwise, and stirred at 1 W ° C for 1 hour. After the reaction was also heated to 0 ° C, a saturated ammonium chloride aqueous solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate · Kiyuan = 1: 2 ~ 1: 1) to obtain 5 · 4 mg (13%) of 6-chloro-7-morpholine-1 as a colorless solid. 4-one-one 3- (2-trifluoromethylphenyl)-2H-isoquinolin-1-one.

] H-NMR (400MHz ^ CDC13) δ (ppm): 3.17 (4H, t, J = 4.6Hz), 3.92 (4H, t, J = 4.6Hz), 6.40 (1H, s), 7.53 (1 H 5 d, J = 7.6 Hz), 7.62— 7.70 (3H, m), 7.82 (lH, d, J = 7.6 Hz), 7.99 (lH, s), 8.62 (1Η, brs)

ESI (LC-MS positive) m / z409 (M + H). [Example 1 5 8] 8-chloro- 7-morpholine- 4-yl-3- (2-trifluoromethylphenyl)-2H-isoamylide- 1 1

Using 2-chloro-6, N-dimethyl-3, morpholine-4 4-ylbenzylamine obtained in Step B of Example 1 5 7 as a raw material, similarly to Step C of Example 15 7 Method. 1H-NMR (400MHz, CDC13) δ (ppm): 3.11 (4H, t, J = 4.4Hz), 3.93 (4H, t'J = 4.4Hz), 6.42 (1H, s -196 -(192) 200536830), 7.40— 7.47 (2H, m), 7.56 (lH, d, J = 7.6Hz), 7.61 (lH, t, J = 7.6Hz), 7.68 (lH, t, J = 7.4 Hz), 7.81 (lH, d, J = 8.0 Hz), 9.00 (lH, brs) ESI (LC-MS positive) m / z4 0 9 (M + H). [Example 1 5 9]

6,8 —dichloro-7 —morpholine 4 4-yl — 3 — (2-trifluoromethylphenyl) — 2H —isoquinoline — 1 monoketone Step A 2, 4-dichloro-6, N —Dimethyl-3-Homo-Lin-4-ylbenzamide

70 mg (0.3 0 mmol) of 2, N-dimethyl-5-morpholine-4-ylbenzamide prepared in step A of Example 157 was dissolved in 2 mL of N, N-dimethylformamide Add 60 mg (0.45 mm ο 1) of N-chlorosuccinimide in an ice bath 'and stir at 0 ° C for 1.5 hours, and at room temperature for 0.5 hours at 50 ° Stir at C for 3 hours. The reaction solution was concentrated, and after adding water, it was extracted with ethyl acetate. The liquid was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained after concentrating the extract was purified by silica gel column chromatography (ethyl acetate: dichloromethane = 1: 5) to obtain 17.4 1 ^ (19%) of 2,4 dichloro-6 as a colorless solid. &gt; 1-dimethyl-1, 3-morphine-4, 1-benzyl benzidine. ] H-NMR (400MHz, CDC13) δ (ppm): 2.27 (3Η, s), 3.03 (3H, d'J = 4.8Hz), 3ll—324 (4Η,]), -197. (193) 200536830 3.8 1 (4H, t, J = 4.6Hz), 5.67 (lH, brs), 7.14 (1Η, s) ESI (LC-MS positive type) m / z303 (M + H).

Step B 6,8 —Dichloro-7 —Moryl — 4 —Methyl — 3 — (2-Dichloromethylphenyl) — 2 Η —Iso-D Quilin — 1 pay

CI 0 was synthesized by a method similar to that in step C of Example 157 using 2,4-dichloro-6, N-dimethyl-3-morpholine-4 4-ylbenzidine as the starting material. Income. ] H-NMR (400MHz, CDC13) (ppm): 3.15-3.18 (2H, m), 3.37-3.42 (2H, m), 3.83-3.91 (4H, m)

, 6.33 (lH, s), 7.49 (lH, s), 7.56 (lH, d, J = 7.2Hz), 7.62-7.71 (2H, m), 7.82 (1H, d, J = 7.6Hz) , 9.39 (1 H, brs) ESI (LC-MS positive) m / z444 (M + H). [Example 160]

6-Fluoro-7-morpholine-4 4-yl-2 3- (2-trifluoromethylphenyl)-2H-iso-isocyanine-1 1 Pay step A -198- (194) 200536830 4 Fluoro-2, N, N-trimethyl-5-morpholine-4-ylbenzamide and 2 monofluoro-6, N, N-trimethyl-6-morpholine-4-ylbenzamide

45 8 mg (1.84 mmol) of a solution of 2, N, N-trimethyl-5-morpholine-4 4-ylbenzamide in 7 mL of acetonitrile prepared in step 80 in an ice bath Add 3 93 mg (1.110 mmol) of N, N —difluoro-2, 2 / —bispyridinebi (tetrafluoroborate), stir at 0 ° C for 1 hour, and stir at room temperature for 1 Hours, stirring at 50 ° C for 1 hour, 80 ° C for 2.5 days, heating and refluxing for 2 hours. Add 3 5 7 mg (1.0 mmol) of Ν, Ν'—bis—2,2'—bislazidine—bis (tetrafluoroborate) and stir for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the residue was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: Kyokudo 2: 1 ~ 3: 1) to obtain 2 5 · 8 mg (5 · 3%) as an oil. Substance 4-1-2, N, N-trimethyl-5-morpholine-4-ylbenzamide and 35.1 (7.2%) oily substance 2-fluoro-6, N, N -Trimethyl- 3 -morpholine-4 -yl benzamidine. 4 monofluoro-2, N ′ N-trimethyl-5-morpholine-4 4-ylbenzylamine] Ν · ΝΜΙΙ (400ΜΗζ, CDC13) δ (ρ ρ ηι): 2.21 (3), 2.84 (3H , S), 3.05 (4H, t, J = 4.6Hz), 3.3H, s), 3.86 (4H, t, J = 4.4Hz) '6.75 (lH'd 8.8 Hz), 6.8S (lH, d, J = 13 · 2Ηζ) -199- (195) 200536830 ESI (LC-MS positive) m / z267 (M + H). 2-Chloro-6, N, N-dimethyl-3-Moryl-4-ylbenzamide 1H-NMR (400MHz, CDC13) δ (ppm): 2.2 1 (3H), 2.92 (3H, s ), 2.93— 2.97 (2H, m), 3.11— 3 (2H, m), 3.17 (3H, s), 3.81-3.90 (4H, m) 6.84 (1H, t, J-8.6Hz), 6.92 (1H, d, J 2: 8 · 4Ηζ)

, S • 32 ESI (LC-MS positive) m / z267 (M + H).

Step B

2H 6-fluoro- 7-morpholine- 4 -yl-3-(2-trifluoromethylphenyl)--isoD-quinolin-1-one

Use 4-fluoro-2, N, N-trimethylmonomorpholine-4-ylbenzamide and 2-fluoro-6, N, N-trimethylmonomorpholine-4 a The benzamidine was synthesized as a raw material by a method similar to that in Step C of Example 157.

j-NMR (400MHz, CDC13) 5 (ppm): 3.2 1 (4H, J = 4.6Hz), 3.92 (4H, t, J = 4.8Hz), 6.41 (1Η), 7.21 (1H, d , J 2 12.8Hz), 7.53 (1H, d,,

7.2Hz), 7.60— 7.69 (2H, in), 7.82 (1H, d, J 8.0Hz), 7.90 (lH, d, J = 7.2Hz), 8.52 (lH, brs) ESI (LC-MS positive) m / z393 (M + H). -200- (196) 200536830 [Example 1 6 1]

8-chloro-1 7-morphine-1 4-yl-1 3-(2-difluoromethylphenyl)-2H-iso-D-quelin-1 1-

F Ο

Using 2-fluoro-6, N, N-trimethyl-1,3-morpholine-4,1-benzamide as the raw material obtained in Step A of Example 1 60, by a method similar to that in Step C of Example 15 7 Synthesized. j-NMR (400MHz, CPC13) 5 (ppm): 3.17-3.20 (4H, m), 3.89-3.91 (4H, m), 6.40 (1H, d, J = 2.0Hz), 7 · 27 — 7.36 (2H, m), 7.53 (1H, d, J = 7.2Hz), 7.5 9 — 7.68 (2H, m), 7.8 1 (1H, d, J = 7.2Hz), 8.40 ((1 H, brs) ESI (LC-MS positive type) m / z393 (M + H). [Example 162] 3-furan-2-yl-7-morpholine 4-yl-1 2H-isoD-quinoline-1 1-one

〇0. Using 5-chloro-2, N, N-trimethylbenzamide obtained in Step A of Example 8 as a starting material, a method similar to that of Example 97-201-(197) 200536830 was used for synthesis. Got. 1 H-NMR (270MHz, DMSO-d6) δ (ppm), t, J = 4.6Hz), 3.77 (4H, t, J = 4.6Hz), (lH, m), 6.88 (lH, s), 7.27 (lH, d,:, 7.45-7.64 (2H, m), 7.80 (lH, s), 11 brs) ESI (LC-MS positive) m / z297 (M + H). : 3.22 (4H 6.62-6.65 [= 3 · 5Ηζ) .38 (1H,

[Example 163] Ketone 2 Trifluoro 7 —Moryl-4 —Methyl — 3 —Pyrididine Didine — 4 —MethylisoD Quilin — 1 — Acetate

Using 5-chloro-2, N-benzamide as the starting material in Step 80 of Example 80, it was obtained by synthesis with Example 97. j-NMR (270 MHz, DMSO-d6) 5 (ppm):, t, J = 4.8Hz), 3.77 (4H, t, J = 4.8Hz),, s), 7.51-7.58 (2H, m), 7.69 (lH, d,), 8.10 (2H, d, J = 5.4Hz), 8.78 (2H, d), 1 1.60 (1H, brs) ESI (LC— MS positive) m / z 308 (M + H-2TF), N-three-page method: 3.28 (4H 7.37 (1H, J = 8.7Ηζ, J = 5 · 4Ηζ -202-(198) 200536830 [Example B-1] [Test Example 1 [Measurement of Cell Proliferation Inhibiting Activity] A representative example of the compound group of the present invention was measured for cell proliferation inhibiting activity.

Cancer cell proliferation inhibiting activity was measured using a Cell Counting Kit-8 manufactured by Tongren Chemical Research Institute Co., Ltd. The human colorectal cancer cell line HCT1 16 obtained from the American Type Culture Collection (Virginia Asia) was planted on a 96-well culture dish, of which 2,000 were in each well, and the compound at a predetermined concentration was added at 37 ° C, 5% C02 culture for 4 days. On the 4th day of the culture, a solution of Cell Counting Kit-8 was added. Measure the absorbance (measurement wavelength is 45 0 nm, reference wavelength is 61 5 nm) based on the procedure attached to the kit, and calculate the 50% cell proliferation inhibition concentration (IC50). ). The results are shown in Table 6.

-203-(199) 200536830 Table 6 Compound number Cell proliferation inhibiting activity (H C T 1 1 6) IC50 (μM) 8 0.028 10 0.097 2 1 0.02 29 0.052 36 0.018 41B 0.034 43B 0.024 61 0.021

[Test Example 2] [Measurement of antitumor effect] Representative examples of the compound group of the present invention were measured for antitumor effect. The antitumor effect was obtained in nude mice BALB / c purchased from Charles River Co., Ltd., A human colorectal cancer cell line HCT 1 16 obtained from the American Type Culture Collection (Virginia Asia, USA) was transplanted into cancer mice subcutaneously in the neck of mice. After the purchased nude mice were subjected to a quarantine period of about 1 week, about 5 × 106 HCT 116 cells were transplanted subcutaneously into the neck of the mice. When the tumor size was about 200 mm3, the mice were provided in the experimental measurement.

The compound was dissolved or suspended in an administration solution and administered orally at 0.5 mL -204- (200) 200536830. The investment is twice after the investment start date and the third day. The anti-tumor effect is compared with the tumor proliferation of the control group administered with the solution, and the tumor proliferation inhibitory effect is calculated. Tumor proliferation inhibitory effect (TGI) = (1 — tumor proliferation in the drug treatment group / tumor proliferation in the control group) X 1 0 0 (%) The results are shown in Table 7

Table 7 Compound No. Antitumor effect D o se (mg / kg) TGI (%) on day 7 8 12.5 96 10 50 91 61 200 73

-205-

Claims (1)

(1) 200536830 10. Scope of patent application1. A compound represented by formula (1), its prodrug, or these salts permitted in the manufacture, characterized in that the compound is represented by formula (n: Y1 (1) [In the formula, Y1 and Y4 represent independently selected from a hydrogen atom and a halogen atom, Y2 and Y3 each represent —nWr2, and the other represents a hydrogen atom or a halogen atom; X represents an aryl group or a heteroaryl group, the The aryl or heteroaryl group may be substituted by 1 or more substituents selected from group A; Group A represents a Ci-8 group (the group may be selected from 1 or 1 or more selected from halogen atoms, aryl groups, heteroaryl groups , 10Rn and a substituent of NR12R13), Ch 7 alkenyl (the Cl 7 alkenyl may be selected from 1 or more halogen atoms, C] -8 alkyl, aryl C! -6 alkyl, Substituted by aryl and heteroaryl substituents), C2_7 alkynyl (the C2_7 alkynyl can be transported from 1 or more from the halogen atom, Ci-8, aryl, square Ci-6, aryl and Heteroaryl substituents), halogen atoms, hydroxyl groups, aryl groups, heteroaryl groups, cyano groups, and amine groups (the amine group may be substituted by 1 or 2 selected from the group consisting of -OR) 1 or -NR12R13 (^ -8 alkyl, aryl, aryl C] -6 alkyl and heteroaryl are substituted based on those substituted on the nitrogen atom), -S (0) nR14 (where η represents an integer from 0 to 2), Alkoxy (the Group is -206- 200536830 (2) Can be substituted with 1 or more substituents selected from aryl, heteroaryl, 1OR] 1 and halogen atoms), 4 to 7-membered heterocyclic groups can be substituted with 1 or more selected from D group Formed by a substituted alkoxy group, a heterophenyloxy group and an alkylene dioxy group; wherein, Rll, Rl2, Rl3, and R14 represent independently selected Ci-8 groups (the alkyl group may be selected from 1 or more than halogen , C〗 -6 alkoxy, amine, c 1-6 alkylamino, dic]., Substituted by aryl and heteroaryl substituents), aryl and: R12 and R13 can be bonded with The nitrogen atom at the junction is connected to form a 4- to 7-membered heterocyclic ring containing a nitrogen atom; R1 represents a C! -8 alkyl group which may be substituted by 1 or 1 selected from a hydrogen atom or B; R2 represents a group selected by 1 or 1 or more Substitute C from Group 8] -8 Yuanji, -COOR3, -COR4, -C0S R5, -NR22R23 or -CRHR25; or R1 and r2 can be connected by nitrogen atom to form 4 ~ containing at least one nitrogen atom] The heterocyclic ring may be selected from 1 or more substituents selected from the group C, where 'R3 represents a hydrogen atom, C] -8 alkyl, c2-7 alkynyl (the alkyl, alkenyl and alkynyl may be 1 or Selected above, hydroxyl 'C!-6 alkoxy (the alkoxy group may be substituted by a ○ or 1 group, C] -6 alkoxy and phenyl substituents), c, aryl and heteroaryl substituents) , (: 3-8 ring, or heteroaryl group; R4 is not selected from hydrogen atom 可由, may be 1 or more R, one nr] 2r] 3 group (the heterocyclic ring), aryl group, self hydrogen atom, atom, A hydroxy-6 alkylamino heteroaryl group; or a conr6r7 substituted with at least 1 group of substituents and a .0-membered heterocyclic ring (substituted); alkenyl, c2_7 from a halogen atom or more It is selected from the group consisting of hydroxy 3-8 cycloalkyl group, -207 substituted by aryl group 20 (3) 200536830 Ci-8 alkyl group, aryl group and heteroaryl group; R5 represents a group selected from hydrogen atom and 0 ^ _8 alkane Aryl, aryl and heteroaryl; R2C) represents a hydroxyl group, a halogen atom, an aryl group, a heteroaryl group, a Ci-6 alkoxy group (the alkoxy group may be substituted by 1 or more substituents selected from a halogen atom, an aryl group, and a heteroaryl group), Aryloxy, heteroaryloxy, amine (the amine group represents that it can be substituted by 1 or more than 1 selected from C ^ -8 alkyl, aryl, aryl C! -6 alkyl, heteroaryl and -COOR21 Substitution based on nitrogen atom) or a 4- to 7-membered heterocyclic group containing at least one nitrogen atom (the heterocyclic group may be substituted by Ci-8 alkyl group); R21 represents an alkyl group, an aryl group (^ -6 alkyl group) Or aryl; R6 and R7 represent independently selected from a hydrogen atom, Chs alkyl, aryl, and heteroaryl; R22 and R23 represent independently selected from a hydrogen atom, Ci-8 alkyl, aryl, and heteroaryl, R24 and R25 represents independently selected from a hydrogen atom, a Chs alkyl group, an aryl group and a heteroaryl group; the B group represents a halogen atom, a C! -6 alkylcarbonyl group, a C! -6 alkylaminocarbonyl group, and a C! -6 alkoxy group Carbonyl group, aryl group (the aryl group means that one or more than one can be selected from a halogen atom, a Ci-8 alkyl group, a C! -8 haloalkyl group, a hydroxyl group, a C! -6 alkoxy group, and a C! -6 haloalkane Substituted by oxo substituents), Heteroaryl, —OR31, and —NR32R33; where R31, R32, and r33 represent independently selected from a hydrogen atom and a C] -8 alkyl group (the alkyl group may be selected from a halogen atom, a hydroxyl group, and C by 1 or more 1-6 alkoxy, aryl, amino, C 1-6 alkylamino and a C 1-6 alkyl -208- (4) 200536830 substituted with amino substituents), aryl, Heteroaryl and a COOR34; represents c] 1 alkyl, times # ^ square group C] -6 alkyl or aryl; or 3 2 3 3 can be bonded to the nitrogen atom to be bonded to form containing at least 1 nitrogen 4 ~ atom, member heterocyclic ring (the heterocyclic group may be substituted by 1 or more groups selected from the group D); group c represents bitter sweet &amp; Group, heteroaryl group, Ci-6 alkyl group, C] -6 alkylamino group C 1 ~ 6 alkoxycarbonyl group, hydroxyl group, C] -8 alkyl group, C! -6 alkoxy group ( The group and alkoxy group may be substituted by 1 or more substituents selected from halogen atom, square group, heteroaryl group, ~ NR4] R42 and _〇r43), aryloxy group and heteroaryloxy group ; Where 'R41, R42, and R43 represent independently selected from a hydrogen atom, Ci-8 alkyl (the group represents that 1 or more can be selected from a halogen atom, a hydroxyl group, C] -6 group oxygen, amine group, ^ Alkylamino and diC] -6 alkylamino substituted by), aryl C! -6 alkyl, aryl and heteroaryl; or R41 and R42 may be connected to the nitrogen atom to which they are bonded To form a 4- to 7-membered heterocyclic ring containing at least one nitrogen atom; the D group represents a member selected from a halogen atom, an aryl group, a heteroaryl group, an aryloxy group, a heteroaryloxy group, and an amine group (the amine group may be selected from 1 or 2 selected from Ci-8 alkyl, hydroxy C] -6 alkyl, C! -6 alkoxy C] -6 alkyl, C! -6 alkyl alkylamino Ci-6 alkyl, di-C ] -6-amino amine C] -6-amino, aryl, aryl C!-6 alkyl and heteroaryl substituents Substituted on the nitrogen atom), hydroxyl group, C! -6 alkoxy group (this alkoxy group means that 1 or more members can be selected from halogen atom, hydroxyl group, C! -6 alkoxy group, and C! -6 alkylamino group And di (: substituted by i-6 alkylamino substituent), C] -6 alkoxycarbonyl, C i-8 alk-209- (5) 200536830 (the alkyl group can be represented by 1 or more than 1 Selected from the group consisting of a halogen atom, a hydroxyl group, a Cl-6 alkoxy group, a C! -6 alkoxycarbonyl group, an amine group, an aryl group, a heteroaryl group, a C! -6 alkylamino group, and a diC! -6 alkylamino group Those substituted by substituents) are represented by []. 2. Such as the compound in the scope of application for patent No. 1, its prodrugs, or these salts which are pharmaceutically approved, wherein Y3 represents -nr] r2. 3. If the compound in the scope of patent application item 1 or item 2, its prodrugs, or these salts which are permitted in pharmacy, wherein Y1, Y2 and Y4 represent hydrogen atom, Y3 represents a NW; X represents aryl or hetero Aryl, which may be substituted by 1 or more substituents selected from group A; group A represents a C! -8 alkyl group (the alkyl group may be substituted by 1 or 1 selected from a halogen atom and a NR] 2R13 Substituted with a halogen atom), a halogen atom, a hydroxyl group, an aryl group, an amine group (the amine group may be substituted by 1 or 2 members selected from a C ^ -8 alkyl group and an aryl group based on a nitrogen atom), an SR14 Ci-6 oxy group (the oxy group can be substituted by 1 or 1 or more substituents selected from -OR11 and halogen atoms), 4- to 7-membered heterocyclic groups (the heterocyclic group can be selected from 1 or 2) The substitution of Ci-8 alkyl and &lt; ^-6 alkoxycarbonyl is based on substitution on the nitrogen atom; wherein, Rn, R12, Rl3, and R14 represent independently selected from a hydrogen atom, C! -8 alkyl and aromatic Or R12 and Ri3 may be connected to the nitrogen atom to be bonded to form a 4- to 7-membered heterocyclic ring containing at least one nitrogen atom; R1 represents that one or more than one may be selected from a hydrogen atom or B Group C-210- (6) 200536830 substituted C;-8 alkyl group; R 2 substituted by group represents a substituted C alkyl group which can be selected from group B or 1 or more COOR: -COR ^ COSR5,-6 r &gt; 7 CONRftR, -NR, "or -N = CRhr25; or ^ and R2 can be connected to the nitrogen atom to be bonded to form 4 ~ 1 () containing at least one nitrogen atom ___ (The heterocyclic ring can be 1 or 1 or more substituted with a substituent selected from the group C); Among them, R3 represents a C! -8 alkyl group (the alkyl group may be selected from 1 or more halogen atoms, a hydroxyl group, a C! -6 alkoxy group (the alkoxy group may be selected from a hydroxyl group, 1 or more groups, (^ — 6 substituted by alkoxy and phenyl substituents, substituted by C 3-8 cycloalkyl, aryl and heteroaryl substituents), C 2-7 Jm groups, C 2-7 alkynyl groups, C 3-8 cycloalkyl, aryl, or heteroaryl; R4 represents a c-8 alkyl, aryl, and heteroaryl group selected from a hydrogen atom and may be substituted by 1 or more ru; R5 is not selected From C] -8 alkyl group and aryl group; r2 () represents a hydroxyl group, a halogen atom, an aryl group, a heteroaryl group, a Ci-6 alkyloxy group, an aryloxy group, an aryl C! -6 alkoxy group, an amine group (the The amine group means that one or two substitutions selected from C! -8 alkyl, aryl, and COOR2 can be substituted on the basis of an atom) or a 4- to 7-membered heterocyclic group containing at least one nitrogen atom (the Heterocyclyl may be substituted by 0] -8 alkyl); R21 represents Ci-8 alkyl, aryl C] -6 alkyl or aryl; R6 and R7 represent independently selected from a hydrogen atom, (:!-8 alkyl , And aryl; R22, R23, R24 and R25 represent independently selected from hydrogen , Courtyard, aryl and heteroaryl; group B represents a halogen atom, C! -6 alkylcarbonyl, aryl, -S1-211-(7) (7) 200536830 and -NR32R33; where 'R3I, r32 and r33 represent independently selected from a hydrogen atom, a Cl_8 alkyl group, an aryl C! -6 alkyl group, an aryl group, a heteroaryl group, and a COR 3 4; r34 represents a Chs alkyl group, an aryl Cl_6 alkyl group, or an aromatic group Or R32 and R33 may be connected to the nitrogen atom to be bonded to form a 4- to 7-membered heterocyclic ring containing at least one nitrogen atom; the C group represents (^ -6 alkylcarbonyl, hydroxyl, C 丨 -8 alkyl , Aryl C] -6 alkoxy C] -8 alkyl, hydroxy C] -8 alkyl, aryloxy and heteroaryloxy. 4. As in the scope of application for patent! Item 3 to item 3 Any one of the compounds, their prodrugs, or these salts that are pharmaceutically acceptable, in which R1 and R2 are bonded to the bonded nitrogen atom to form a 4 to 10-membered heterocyclic ring containing at least} nitrogen atoms, the hetero The ring may have a substituent selected from the group C. 5 · As a compound of any one of claims 1 to 4 of the scope of patent application, a prodrug thereof, or a pharmaceutically acceptable salt thereof, which is Y2 or Y3? Phenolinyl, azetidine, pyrrolyl or piperidinyl, the heterocyclic group may be substituted by 1 or more substituents selected from the group consisting of hydroxyl or hydroxy C! -6 alkyl. The compound according to any one of items 5 to 5, a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Y2 or Y3 is morpholinyl, azetidine, pyrrolyl, 3-hydroxypyrrolyl, 2-hydroxymethylpyrrolyl, 3-hydroxymethylpyrrolyl, piperidinyl, 3-hydroxypiperidinyl, 4-hydroxypiperidinyl, 2-hydroxymethylpiperidinyl, 3-hydroxytylmethyl vein η-Amidyl, 4-Aminomethyl-E-Damino, or 4-Arylidene-4-A-212-200536830 (8) ylmethylpiperidinyl. 7. The compound of any one of claims 1 to 3, its prodrug, or these salts which are pharmaceutically approved, wherein R1 is a hydrogen atom or an 8 alkyl group (the alkyl group may be 1 or 1) The above is substituted with a substituent selected from the B group); R2 is a C1 —alkyl group, a COOR3 or —COCH2NHCOOR21 substituted with 1 or more substituents selected from the B group. ♦ 8. If the compound of any one of items 1 to 3 of the scope of patent application, its prodrugs, or these salts which are pharmaceutically approved, wherein R 1 is a hydrogen atom; R 2 is a COOR3, a COSR5, a CONR6R7 or a COR4. 9. The compound of any one of claims 1 to 3, its prodrug, or these salts which are pharmaceutically approved, wherein R2 is ~ COOR3. 1 10. If the compound in the ninth scope of the application for a patent, its prodrug, ®, or these salts which are pharmaceutically acceptable, wherein Chi 3 is alkyl, C2-7 alkenyl, c2-7 alkynyl, the alkyl, Alkenyl and alkynyl can be selected from 1 or 1 selected from halogen atom, mesityl, C] -6 alkoxy (the oxo is selected from 1 or 1 selected from hydroxyl, c 1-6 alkoxy and phenyl (11) Such as the compounds in the scope of application for patent No. 10, its prodrugs, or these salts which are pharmaceutically approved, wherein R3 is 1 or;! The C] -8 alkyl group substituted by the above hydroxyl group, a C.2-7 alkenyl group substituted by a hydroxyl group of 1 or more, or a C2-7 alkynyl group substituted by a hydroxyl group of 1 or more. -213- 200536830 (9) 1 2 · If the compound in the scope of patent application No. 11, its precursor ^%, or these salts that are pharmaceutically approved, where R3 is C substituted by 1 or more hydroxyl groups! -6 alkyl. 13. If the scope of the application for patents 1 to 3 and 7 {{non ~ compounds, their prodrugs, or pharmacologically licensed ^ ^ # in which Y2 or Y3 is bis (hydroxy Cl_ 6 alkane Group) amino group, methyl (hydroxy C-6 alkyl) amino group, hydroxyl C!-6 alkyl amino group, methyl (Malco ^ C!-6 alkyl) amino group, amino group C! — 6 alkylamino, C 6 alkoxyfrequency amino, or hydroxy C! -6 alkoxycarbonylamino. 1 4 · If the compound of any one of items 1 to 3, 7, and 8 of the scope of patent application, its prodrug, or these salts are pharmaceutically approved, in which Y2 or Y3 is a double (2 Monohydroxyethyl) amino, methyl (2 monohydroxyethyl) amino, 2-hydroxyethylamino, methyl (2-morpholine-4 monoethyl) amino, methyl (2- Aminoethyl) amino or 2-hydroxyethyloxycarbonylamino. 15 · If the compound of any one of items 1 to 14 of the scope of patent application, its prodrug, or these salts are pharmaceutically acceptable, wherein X is phenyl or heteroaryl, the phenyl or heteroaryl The aryl group may be substituted with 1 or more substituents selected from the group A. 16 · If the compound of any one of items 1 to 14 of the scope of patent application, its prodrug, or these salts which are pharmaceutically approved, wherein X is a phenyl group, the phenyl group may be 1 or more than 1 Substituted by a substituent selected from Group A. 1 7 · If any one of the scope of application for the first to the 14th of the scope of the patent application -214- 200536830 (10) compounds, their prodrugs, or these salts are pharmaceutically approved, where χ is phenyl or Heteroaryl, the phenyl or heteroaryl is substituted by 1 or 1 or more substituents selected from group A; Group A is C 1 -8 or aryl groups substituted by 1 or more halogen atoms , C] -6 alkylthio, diC! -6 alkylamino, 4- to 7-membered heterocyclic groups containing at least one nitrogen atom, C] -8 alkyl, C2-7 alkyl, Cl 7 alkynyl, Cl-6 alkoxy (this alkoxy may be substituted by a halogen atom of 1 or more) and a hydroxyl group. 18 · If the compound of any one of items 1 to 17 of the scope of patent application, its prodrug, or these salts are pharmaceutically approved, where χ represents a phenyl group, and the phenyl group can be 1 or more than 1 Substitutions selected from ethyl, trifluoromethyl, dioxymethoxy, methylthio, methoxy, chloro, phenyl, dimethylamino, morpholinyl, pyrrolyl and piperidinyl Group. 1 9 · A compound characterized by a compound represented by the formula w; 0 IV (where 'X represents a phenyl or heteroaryl group, the phenyl or heteroaryl group may be selected from the group A by 1 or more Substituted by a substituent; L represents a halogen atom at the 6th or 7th position bonded to the isolinone ring. 2 ·· A method for producing a compound such as the first item of the patent scope, which is characterized by The amination step of the compound in the scope of the patent No. 9 2 1 ·-a kind of pharmaceutical composition, which is characterized in that any of the scope of the patent scope of the application} -215- (11) (11) 200536830 to the 18th A compound, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 22 · —A therapeutic agent and a preventive agent for malignant tumors, characterized in The compound according to any one of the above items, its precursors, or these salts which are pharmaceutically acceptable as an active ingredient. 2 3 · The therapeutic agent and preventive agent according to item 22 of the patent application scope, wherein the malignant tumor is solid cancer. -216- 200536830 Wuming said that the single abbreviation symbol table is the definitive figure designation table of the original drawing table: the case plan, the present generation / the set one or two refers to CC, no problem, if there is a chemical formula in this case, please disclose the best Chemical formula showing the features of the invention: Y1 (1)-5-